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Starvation tactics using natural compounds for advanced cancers: Pharmacodynamics, clinical efficacy, and predictive biomarkers
Cancer Medicine
Abstract
The high mortality associated with oncological diseases is mostly due to tumors in advanced stages, and their management is a major challenge in modern oncology. Angiogenesis is a defined hallmark of cancer and predisposes to metastatic invasion and dissemination and is therefore an important druggable target for cancer drug discovery. Recently, because of drug resistance and poor prognosis, new anticancer drugs from natural sources targeting tumor vessels have attracted more attention and have been used in several randomized and controlled clinical trials as therapeutic options. Here, we outline and discuss potential natural compounds as salvage treatment for advanced cancers from recent and ongoing clinical trials and real‐world studies. We also discuss predictive biomarkers for patients' selection to optimize the use of these potential anticancer drugs.
Supplementary resource (1)
... This anticancer natural compound was investigated alone or in combination with other chemotherapeutics in clinical trials and showed signs of activity [34,35]. In the clinic, this drug has been approved for treating soft tissue sarcomas and platinum-sensitive OC [27,36]. Interestingly, some translational reports provided evidence supporting the use of some genetic alterations to predict the efficacy of trabectedin [36]. ...
... In the clinic, this drug has been approved for treating soft tissue sarcomas and platinum-sensitive OC [27,36]. Interestingly, some translational reports provided evidence supporting the use of some genetic alterations to predict the efficacy of trabectedin [36]. This review summarizes the current findings on the molecular mechanism and predictive biomarkers of trabectedin response in gynecologic oncology. ...
... Several recent studies showed that trabectedin is devoted to a complex and pleiotropic mechanism of action [36,37]. This unique cytotoxic agent interacts with the DNA double helix minor groove, affects several genes involved in the DNA repair system and facilitates the generation of lethal DNA strand breaks leading therefore to cell death [32,38]. ...
The use of predictive biomarkers provides potential individualized cancer therapeutic options to prevent therapy failure as well as serious toxicities. Several recent studies showed that predictive and prognostic biomarkers are a notable personalized strategy to improve patients’ care in several cancers. Trabectedin (Yondelis®) is a cytotoxic agent, derived from a marine organism, harbouring a significant antitumor activity against several cancers such as soft tissue sarcoma, ovarian, and breast cancers. Recently and with the advent of molecular genetic testing, BRCA mutational status was found as an important predictor of response to this anticancer drug especially in gynecological cancers. The aim of this updated review is to discuss the mechanisms of action of trabectedin against the well-known cancer hallmarks described until today. We also examined the current advances related to genomic biomarkers that can be used in the future to predict the efficacy of this potent anticancer natural molecule in various gynecological cancers.
... Previously, diverse anticancer natural compounds tested in randomized and controlled trials alone or in combination with other chemotherapeutics have shown some durable clinical response in cancer patients with advanced stages [10][11][12][13]. However, their current use in cancer drug discovery and daily practice is still facing many challenges such as serious toxicities and acquired drug resistance, and their clinical efficacy in early human clinical trials often remains limited. ...
... Unfortunately, natural anticancer compounds have not yet benefited from the recent advances related to predictive biomarkers compared to targeted therapies. Promisingly, some recent reports about biomarkers have emerged in modern oncology to reliably predict efficacy and adverse drug reactions as well as to enable patients' selection who will likely respond to these nature-derived therapeutic agents [10,14,15] ( Table 1 tumor tissue biomarkers including mutated ERCC5, ERCC1, and BRCA1 were initially investigated in soft tissue sarcoma (STS) patients enrolled in two phase II trials and treated with trabectedin (Yondelis ® , Phar-maMar), an alkaloid derived from the Caribbean tunicate Ecteinascidia turbinata [16]. Trabectedin (a) causes DNA damages, (b) alters tumor blood flow, (c) inhibits angiogenesis by activating TIMP1 (tissue inhibitor of metalloproteinase 1) and TIMP2 (tissue inhibitor of metalloproteinase 2), (d) alters BRCA genes and exerts blockade of other cancer signaling pathways [10]. ...
... Promisingly, some recent reports about biomarkers have emerged in modern oncology to reliably predict efficacy and adverse drug reactions as well as to enable patients' selection who will likely respond to these nature-derived therapeutic agents [10,14,15] ( Table 1 tumor tissue biomarkers including mutated ERCC5, ERCC1, and BRCA1 were initially investigated in soft tissue sarcoma (STS) patients enrolled in two phase II trials and treated with trabectedin (Yondelis ® , Phar-maMar), an alkaloid derived from the Caribbean tunicate Ecteinascidia turbinata [16]. Trabectedin (a) causes DNA damages, (b) alters tumor blood flow, (c) inhibits angiogenesis by activating TIMP1 (tissue inhibitor of metalloproteinase 1) and TIMP2 (tissue inhibitor of metalloproteinase 2), (d) alters BRCA genes and exerts blockade of other cancer signaling pathways [10]. Trabectedin generates double-strand breaks in DNA and with the inability to repair these altered structures; cancer cells undergo rapid cell death, a recent concept known as synthetic lethality. ...
Intrinsic or acquired drug resistance, adverse drug reactions and tumor heterogeneity between and within cancer patients limit the efficacy of clinical management of advanced cancers. To overcome these barriers, predictive biomarkers have recently emerged to guide medical oncologists in the selection of cancer patients who will respond to various anticancer treatments and to improve the toxicity to benefit ratio. Notably, targeted therapy has significantly benefited from these advances, but the application of predictive biomarkers have been a bit slower with some drugs derived from natural sources such as trabectedin, cabazitaxel and alvocidib. In this paper, we discuss some recent advances regarding the use of cancer biomarkers to predict efficacy of some selected natural compounds with a focus on human clinical studies.
... Plitidepsin (also known as dehydrodidemnin B) is a natural compound discovered in a Caribbean marine organism (Aplidium albicans) [48]. Its antitumour effects encompass several cancer targets such as angiogenesis and cell survival [5,72]. ...
... The activation of c-Jun N-terminal kinase is a key mediator of plitidepsin sensitivity along with the eukaryotic elongation factor 1 alpha 2 that were recently suggested as potential predictive biomarkers of drug response [50,126]. So far, the drug has been investigated in several clinical trials for multiple myeloma, lymphoma, liposarcoma and prostate cancer [48]. Only one phase III randomised and controlled trial has evaluated the clinical activity of plitidepsin combined to dexamethasone in relapsed/refractory multiple myeloma (NCT01102426/ADMYRE), showing mild improvements in survival outcomes [180]. ...
Since its outbreak in the last December, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has rapidly spread worldwide at a pandemic proportion, thus regarded as a global public health emergency. The existing therapeutic options for COVID-19 beyond the intensive supportive care are limited, with an undefined or modest efficacy reported so far. Drug repurposing represents an enthusiastic mechanism to use approved drugs outside the scope of their original indication and accelerate the discovery of new therapeutic options. With the emergence of COVID-19, drug repurposing has been largely applied for early clinical testing. In this Review, we discuss some repurposed anticancer drugs for the treatment of COVID-19 and under investigation in clinical trials or proposed for the clinical testing. .
... Therefore, treatment to combat this disease was needed urgently. Hence, most developed countries invested many in pharmaceutical and academic institutions to foster the research and development of drugs or vaccines to treat millions of infected young and old people from different countries and ethnicities [15]. As a result, the FDA approved the use of various drugs known for treating other diseases, such as malaria. ...
The coronavirus disease 2019 (COVID-19) outbreak resulted in an economic burden, with millions of morbidity and mortality infections, due to the unavailability of treatment and limited resources in many developing countries. Drug repurposing was among the first ways to come up with a solution to combat the COVID-19 outbreak worldwide and save lives. Drug repurposing, well-defined as investigating new hints for approved drugs or progressing formerly considered but unapproved drugs, is the main approach in drug development. It is suggested that at least 30–40% of novel drugs and biologics permitted by the US Food and Drug Administration (FDA) in 2007 and 2009 can be considered repurposed or repositioned products. Here, we discuss some of the proposed and tested drugs as tools to eliminate COVID-19, the challenges and successes of preparing for future pandemics using the drug repurposing approach, and treating other diseases.
... However, room for improvements is still wide, as the outcomes of some cancer patients are still poor, despite the best treatments received. With their predictive and prognostic potential, genomic and proteomic biomarkers have gained a significant role in the management of cancer patients, to optimize patients' selection and improve the efficacy to toxicity ratio [1][2][3][4]. Beyond the tumor intrinsic oncogenic characteristics, driving the clinical behavior, additional factors related to the host, and the external environment can impact on the response and efficacy of antineoplastic treatments. ...
Introduction: The gut microbiota seems to play a key role in tumorigenesis, across various hallmarks of cancer. Recent evidence suggests its potential use as a biomarker predicting drug response and adding prognostic information, generally in the context of immunooncology.
Areas covered: In this review we focus on the modulating effects of gut-microbiota dysbiosis on various anticancer molecules used in practice, including cytotoxic and immunemodulating agents, primarily immune-checkpoint inhibitors (ICI). Pubmed/Medline-based literature search was conducted to find potential original studies that discuss gut microbiota as a prognostic and predictive biomarker for cancer therapy. We also looked at the US ClinicalTrials.gov website to find additional studies particularly ongoing human clinical trials.
Expert opinion: Sequencing of stool-derived materials and tissue samples from cancer
patients and animal models has showna significant enrichment of various bacteria such as Fusobacterium nucleatum and Bacteroides fragilis were associated with resistant disease and poorer outcomes. Gut microbiota was also found to be associated with surgical outcomes and seems to play a significant role in anastomotic leak (ATL) after surgery mainly by collagen breakdown. However, this research field is just at the beginning and the current findings are not yet ready to change clinical practice.
... Nurul Hidayah Wahab et al./ Asian Pacific Journal of Tropical Biomedicine 2019; 9(8): 339-345 interleukin-6 (IL-6), and anti-inflammatory mediators such as IL-12 [5]. Due to the adverse effects caused by chemically synthetic drugs, the development of new anticancer drugs originated from natural products has drawn scientist's attention [6]. Oroxylum indicum (O. ...
... HPV-induced chronic inflammation is closely associated with the imbalance secretion of pro-inflammatory cytokines such as interleukin-6 (IL-6), and anti-inflammatory mediators such as IL-12 [5]. Due to the adverse effects caused by chemically synthetic drugs, the development of new anticancer drugs originated from natural products has drawn scientist's attention [6]. Oroxylum indicum (O. ...
Objective: To examine the proapoptotic properties of Oroxylum indicum methanol extract on cervical cancer cells.
Methods: Methylene blue assay was used to determine the IC50 value of the extract. Western blotting assays were done to analyze the expression of HPV oncoproteins (HPV18 E6 and E7) and apoptotic molecules (caspase-3 and caspase-8). Reverse transcriptase PCR assays were performed to determine genetic alteration of tumor suppressors p53 and pRb and apoptosis markers Fas and FasL. Enzyme-linked immunosorbent assay (ELISA) was done to determine the expression of cytokine levels (IL-6 and IL-12).
Results: The determination of IC50 value indicated a higher anti-proliferative activity of the extract compared to cisplatin. After 24 hours of treatment, Western blot analysis showed that treated HeLa cells exhibited a significant down-regulation of HPV18 oncoproteins E6 and E7, and a significant induction of caspase-8 and caspase-3 activation level. Meanwhile, the mRNA expressions of p53, pRb, Fas and FasL were significantly upregulated in treated cells. Moreover, ELISA showed an increased IL-12 and decreased IL-6 production after Oroxylum indicum treatment.
Conclusions: The methanol extract of Oroxylum indicum has an anti-proliferative activity and proapoptotic potential. It induces localized-immunity improvements by altering cytokine production in HPV-positive cervical cancer cells.
The concept of drug repurposing has been introduced in this chapter (Sect. 13.8) as a new strategy for MTD drug discovery based on “promising promiscuity.” Here in this chapter, a different prospect of drug repurposing will be discussed by highlighting the latest applications of drug repurposing in various diseases in the clinical settings exemplified by some representative repurposed drugs for comparison of old and new therapeutic uses, with the assessment of their novel mechanisms of action and pharmacological effects in the management of various disorders; specifically, the applications of repurposed drugs to the treatment of cancer, cardiovascular disease, metabolic disorders, Alzheimer’s disease, COVID-19, and rare diseases. Finally, the drug repurposing from the perspective of pharmaceutical industries will be discussed.KeywordsDrug repurposingCancerCardiovascular diseaseRare and orphan diseasesCOVID-19
Since the emergence of data about the natural history of ovarian cancer (OC) approximately 150 years ago, tremendous advances have been made in the area of the molecular pathology of this aggressive cancer. However, OC remains one of the most lethal gynecological cancers worldwide, with no adequate screening and prevention program available yet to avoid diagnosis in advanced stages. Despite OC still being the silent killer, it has seen dynamic shifts in its classification, staging, and theories regarding its origins in the last years. In fact, the term OC has experienced a shift to include primary peritoneal and tubal cancer, as these tumors behave identically. The prognosis and treatment of OC are dependent on multiple factors, including tumor biology and extent of tumor spread, which has recently been reclassified in a new FIGO staging system. In the literature throughout the years, attempts to identify the origins of these heterogeneous tumor entities have better guided our diagnostic strategies and therapeutic arsenal. This chapter aims to give a general overview of the epidemiology, the natural history as well as the pathology of epithelial OC.
The development of the conceptual cancer hallmarks has deeply changed our understanding of cancer initiation, progression, and metastasis. Moreover, this pivotal effort is a milestone that provided the scientific rationale for developing new cancer biomarkers and anticancer drugs. In ovarian cancer (OC), the ten cancer hallmarks described by Hanahan and Weinberg were investigated in translational studies for prognostic and predictive biomarker discovery. In addition, several interventional clinical trials used these principles to explore the clinical efficacy of several chemotherapeutic and targeted agents such as antiangiogenics and PARP inhibitors. Promisingly, survival outcomes in women with OC were improved with the arrival of novel single agents and combinatorial approaches. In this chapter, the clinical impact of genetics, biomarkers, and therapy in OC is reviewed based on the hallmarks of cancer. We particularly present a special emphasis on druggable targets investigated in phase II/III clinical trials for OC.
This book comprehensively summarizes the biology, etiology, and pathology of ovarian cancer and explores the role of deep molecular and cellular profiling in the advancement of precision medicine. The initial chapter discusses our current understanding of the origin, development, progression and tumorigenesis of ovarian cancer. In turn, the book highlights the development of resistance, disease occurrence, and poor prognosis that are the hallmarks of ovarian cancer. The book then reviews the role of deep molecular and cellular profiling to overcome challenges that are associated with the treatment of ovarian cancer. It explores the use of genome-wide association analysis to identify genetic variants for the evaluation of ovarian carcinoma risk and prognostic prediction. Lastly, it highlights various diagnostic and prognostic ovarian cancer biomarkers for the development of molecular-targeted therapy.
The emergence of precision medicine and our latest understanding of the biological characteristics of ovarian cancer (OC) have led to the discovery of drug targets, novel anticancer agents, and their predictive biomarkers. The genetics of OC is an evolving biomarker for predicting outcomes. Several completed and ongoing clinical trials used this concept for better patients’ selection and stratification. The exploitation of specific molecular vulnerabilities in OC for drug development such as BRCA and BRCAness is a milestone in the current management of this women’s cancer. Without a doubt, OC is one of the solid cancers that have benefited from genetic biomarkers for the implementation of targeted agents such as PARP inhibitors in clinical practice. This progress is discussed in this chapter based on recent studies and clinical trials.
Blood vessels in the tumor periphery have high pericyte coverage and are resistant to vascular disrupting agents (VDAs). VDA treatment resistance leads to a viable peripheral tumor rim that contributes to treatment failure and disease recurrence. Here, we provide evidence to support a hypothesis that shifting the target of VDAs from tumor vessel endothelial cells to pericytes disrupts tumor peripheral vessels and the viable rim, circumventing VDA treatment resistance. Through chemical engineering, we developed Z-GP-DAVLBH (from the tubulin-binding VDA desacetylvinblastine monohydrazide [DAVLBH]) as a prodrug that can be selectively activated by fibroblast activation protein α (FAPα) in tumor pericytes. Z-GP-DAVLBH selectively destroys the cytoskeleton of FAPα-expressing tumor pericytes, disrupting blood vessels both within the core and around the periphery of tumors. As a result, Z-GP-DAVLBH treatment eradicated the otherwise VDA-resistant tumor rim and led to complete regression of tumors in multiple lines of xenografts without producing the drug-related toxicity that is associated with similar doses of DAVLBH. This study demonstrates that targeting tumor pericytes with an FAPα-activated VDA prodrug represents a potential vascular disruption strategy in overcoming tumor resistance to VDA treatments.
Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.
Specific alkylators may allow synthetic lethality among patients with germline BRCA1/2-mutations related cancers. The tetrahydroisoquinolone trabectedin administered at 1.3 mg/m² as a 3-h intravenous infusion every 3 weeks showed activity in patients with pretreated metastatic breast cancer (MBC) and BRCA germline mutations, but mainly in BRCA2 carriers. Data from a phase II study were retrospectively analyzed to compare the efficacy and safety of this trabectedin dose and schedule in pretreated MBC patients bearing germline BRCA1/2 mutations. The primary efficacy endpoint was the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST) by independent expert review. Duration of response (DR) and progression-free survival (PFS) were secondary efficacy endpoints. Safety was evaluated using the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Data from 26 BRCA1-mutated and 13 BRCA2-mutated patients were analyzed. 69% of BRCA1-mutated cancers were triple-negative vs. 31% of BRCA2-mutated ones. 77% of BRCA1 and 31% of BRCA2 carriers were platinum-pretreated. The ORR in BRCA2-mutated patients was higher than in BRCA1-mutated patients (33.3% vs. 9.1%). DR ranged for 1.4–6.8 months in BRCA2-mutated patients and for 1.5–1.7 months in BRCA1-mutated patients. More BRCA2-mutated patients had disease stabilization for ≥4 months (25.0% vs. 9.1%) and their median PFS was longer (4.7 vs. 2.5 months). Trabectedin was well tolerated in both patient subtypes. In conclusion, trabectedin showed higher antitumor activity in relapsed MBC patients with germline BRCA2 mutations than in those with BRCA1 mutations.
Combination vascular-targeted therapies (VTTs) represent a promising approach for patients with platinum-resistant recurrent ovarian cancer (OC). VTTs include two mechanistically distinct classes of agents: anti-angiogenic agents (AAs) and vascular-disrupting agents (VDAs). AAs suppress growth of new tumor vasculature through inhibition of vascular endothelial growth factor (VEGF) and other pro-angiogenic molecules. Bevacizumab, a monoclonal antibody that binds to VEGF, has improved progression-free survival (PFS) when given with chemotherapy in patients with advanced OC. VDAs target the established tumor vascular network, inducing vessel occlusion, shutdown of circulation, and widespread necrosis within the tumor interior – a region often resistant to conventional chemotherapy and radiation. Tubulin-binding VDAs such as BNC105P, ombrabulin, and combretastatin A4-phosphate (CA4P) have been studied for the treatment of OC. These agents act by binding tubulin in the endothelial cells of tumor vessels, triggering cytoskeletal disruption, altering cellular shape, and destabilizing cell–cell junctions, which lead to increased vascular leakage and, ultimately, to disruption of blood flow. Fundamental differences between the vascular networks of tumors and those of normal tissues allow these agents to selectively reduce tumor circulation while having little effect on non-malignant tissues. Animal studies and clinical trials show enhanced efficacy when VDAs are combined with chemotherapy as well as AAs. The latter combination allows targeting of different aspects of the tumor vasculature, a strong rationale for combining these two drug classes into a single regimen. CA4P is the only VDA in active development for OC. In a phase II trial of patients with recurrent OC, CA4P added to bevacizumab improved PFS compared with bevacizumab alone. The phase II, placebo-controlled PAZOFOS trial (NCT02055690) is evaluating the effects of CA4P plus the anti-angiogenic agent pazopanib in recurrent OC. FOCUS, a phase II/III, placebo-controlled trial (NCT02641639), is currently evaluating CA4P plus bevacizumab and chemotherapy in platinum-resistant OC.
Plitidepsin is a cyclic depsipeptide that was first isolated from a Mediterranean marine tunicate (Aplidium albicans) and, at present, is manufactured by total synthesis and commercialized as Aplidin®. Its antitumor activity, observed in preclinical in vitro and in vivo studies has prompted numerous clinical trials to be conducted over the last 17 years, alone or in combination with other anticancer agents. Single-agent plitidepsin has shown limited antitumor activity and a tolerable safety profile in several malignancies, such as noncutaneous peripheral T-cell lymphoma, melanoma, and multiple myeloma. In patients with relapsed or refractory multiple myeloma, plitidepsin activity seems to be enhanced after addition of dexamethasone while remaining well tolerated, and a Phase III trial comparing plitidepsin plus dexamethasone vs dexamethasone alone is underway. Additional studies are required to better define the role of plitidepsin in combination with other active agents in these indications. Results of plitidepsin activity in other hematological malignancies or solid tumors have been disappointing so far. Further studies analyzing its mechanisms of action and potential biomarkers will help select patients who may benefit most from this drug. In this review, we critically analyze the published studies on plitidepsin in hematological malignancies and solid tumors and discuss its current role and future perspectives in treating these malignancies. We also review its design, pharmaceutical data, and mechanism of action.
This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients. The study included two treatment arms: a sorafenib/plitidepsin (S/P) and a gemcitabine/plitidepsin (G/P) arm. In the S/P arm, patients were treated orally with sorafenib continuous dosing at two dose levels (DL1: 200 mg twice daily and DL2: 400 mg twice daily) combined with plitidepsin (1.8 mg/m, day 1, day 8, day 15, and, q4wk, intravenously). In the G/P arm, patients with solid tumors or lymphoma were treated at four different DLs with a combination of gemcitabine (DL1: 750 mg/m, DL2-DL4: 1000 mg/m) and plitidepsin (DL1-DL2: 1.8 mg/m; DL3: 2.4 mg/m; DL4: 3 mg/m). Both agents were administered intravenously on day 1, day 8, day 15, and, q4wk. Forty-four patients were evaluable for safety and toxicity. The safety of the combination of plitidepsin with sorafenib or gemcitabine was manageable. Most adverse events (AEs) were mild; no grade 4 treatment-related AEs were reported in any of the groups (except for one grade 4 thrombocytopenia in the gemcitabine arm). The most frequently reported study drug-related (or of unknown relationship) AEs were palmar-plantar erythrodysesthesia, erythema, nausea, vomiting, and fatigue in the S/P arm and nausea, fatigue, and vomiting in the G/P arm. In the S/P arm, one dose-limiting toxicity occurred in two out of six patients treated at the maximum dose tested (DL2): palmar-plantar erythrodysesthesia and grade 2 aspartate aminotransferase/alanine aminotransferase increase that resulted in omission of days 8 and 15 plitidepsin infusions. In the G/P arm, one dose-limiting toxicity occurred in two out of six patients at DL4: grade 2 alanine aminotransferase increase resulted in omission of days 8 and 15 plitidepsin infusions and grade 4 thrombocytopenia. The recommended dose for the combination of plitidepsin with sorafenib was not defined because of a sponsor decision (no expansion cohort to confirm) and for plitidepsin with gemcitabine, it was 2.4 mg/m plitidepsin with 1000 mg/m gemcitabine. In the S/P group, objective disease responses were not observed; however, disease stabilization (≥3months) was observed in four patients. In the gemcitabine group, two lymphoma patients showed an objective response (partial response and complete response) and nine patients showed disease stabilization (≥3months). Combining plitidepsin with gemcitabine and sorafenib is feasible for advanced cancer patients; some objective responses were observed in heavily pretreated lymphoma patients.
Introduction
Combretastatin A4-phosphate, fosbretabulin tromethamine (CA4P) is a vascular disrupting agent that targets tumor vasculature. This study evaluated the safety of CA4P when combined with carboplatin, paclitaxel, and bevacizumab in chemotherapy-naïve subjects with advanced nonsquamous, non-small-cell lung cancer.
Methods
Adult subjects with confirmed American Joint Committee on Cancer six stage IIIB/IV non-small-cell lung cancer and an Eastern Cooperative Oncology Group performance score of 0 or 1 were randomized to receive six cycles (treatment phase) of paclitaxel (200 mg/m²), carboplatin (area under the concentration versus time curve 6), and bevacizumab (15 mg/kg) on day 1 and repeated every 21 days, or this regimen plus CA4P (60 mg/m²) on days 7, 14, and 21 of each cycle. Subjects could then receive additional maintenance treatment (excluding carboplatin and paclitaxel) for up to 1 year.
Results
Sixty-three subjects were randomized, 31 to control and 32 to CA4P, and 19 (61.3%) and 17 (53.1%), respectively, completed the treatment phase. Exposure to study treatment and dose modifications were comparable between the randomized groups. The overall incidence of treatment-emergent adverse events was similar between groups, with increased neutropenia, leukopenia, and hypertension in the CA4P group. Deaths, serious adverse events, and early discontinuations from treatment were comparable between the randomized treatment groups. The overall tumor response rate with CA4P was 50% versus 32% in controls. Overall and progression-free survival rates were comparable between the groups.
Conclusion
CA4P plus carboplatin, paclitaxel, and bevacizumab appears to be a tolerable regimen with an acceptable toxicity profile in subjects with advanced non-small-cell lung cancer.
Carcinoma cells can acquire increased motility and invasiveness through epithelial-to-mesenchymal transition (EMT). However, the significance of EMT in cancer metastasis has been controversial, and the exact fates and functions of EMT cancer cells in vivo remain inadequately understood. Here, we tracked epithelial cancer cells that underwent inducible or spontaneous EMT in various tumor transplantation models. Unlike epithelial cells, the majority of EMT cancer cells were specifically located in the perivascular space and closely associated with blood vessels. EMT markedly activated multiple pericyte markers in carcinoma cells, in particular PDGFR-β and N-cadherin, which enabled EMT cells to be chemoattracted towards and physically interact with endothelium. In tumor xenografts generated from carcinoma cells that were prone to spontaneous EMT, a substantial fraction of the pericytes associated with tumor vasculature were derived from EMT cancer cells. Depletion of such EMT cells in transplanted tumors diminished pericyte coverage, impaired vascular integrity, and attenuated tumor growth. These findings suggest that EMT confers key pericyte attributes on cancer cells. The resulting EMT cells phenotypically and functionally resemble pericytes and are indispensable for vascular stabilization and sustained tumor growth. This study thus proposes a previously unrecognized role for EMT in cancer.
eEF1A2 is one of the isoforms of the alpha subunit of the eukaryotic Elongation Factor 1. It is overexpressed in human tumors and is endowed with oncogenic properties, favoring tumor cell proliferation while inhibiting apoptosis. We demonstrate that plitidepsin, an antitumor agent of marine origin that has successfully completed a phase-III clinical trial for multiple myeloma, exerts its antitumor activity by targeting eEF1A2. The drug interacts with eEF1A2 with a KD of 80 nM and a target residence time of circa 9 min. This protein was also identified as capable of binding [¹⁴C]-plitidepsin in a cell lysate from K-562 tumor cells. A molecular modelling approach was used to identify a favorable binding site for plitidepsin at the interface between domains 1 and 2 of eEF1A2 in the GTP conformation. Three tumor cell lines selected for at least 100-fold more resistance to plitidepsin than their respective parental cells showed reduced levels of eEF1A2 protein. Ectopic expression of eEF1A2 in resistant cells restored the sensitivity to plitidepsin. FLIM-phasor FRET experiments demonstrated that plitidepsin localizes in tumor cells sufficiently close to eEF1A2 as to suggest the formation of drug-protein complexes in living cells. Altogether, our results strongly suggest that eEF1A2 is the primary target of plitidepsin.
Objective
In clinical studies in Western countries, the recommended dose of combination ombrabulin a vascular disrupting agent, with cisplatin is 25 mg/m² ombrabulin with 75 mg/m² cisplatin every 3 weeks. Here, we report the first Phase 1 study of this treatment regimen in Japanese patients with advanced solid tumors.
Methods
This was an open-label, multicenter, sequential cohort, dose-escalation Phase 1 study of ombrabulin with cisplatin administered once every 3 weeks. The study used a 3 + 3 design without intrapatient dose escalation. The investigated dose levels of ombrabulin were 15.5 and 25 mg/m² combined with cisplatin 75 mg/m². The latter dose level was regarded as the maximum administered dose if more than one patient experienced dose-limiting toxicities.
Results
Ten patients were treated, but no dose-limiting toxicity was observed at both dose levels. Ombrabulin 25 mg/m² with cisplatin 75 mg/m² was the maximum administered dose and regarded as the recommended dose in the combination regimen for Japanese patients with cancer. The most frequently reported drug-related adverse events were neutropenia, decreased appetite, constipation, nausea and fatigue. One partial response and five cases of stable disease were reported as the best overall responses. Pharmacokinetic parameters of ombrabulin and cisplatin were comparable with those in non-Japanese patients.
Conclusions
Ombrabulin 25 mg/m² with cisplatin 75 mg/m² once every 3 weeks was well tolerated and established as the recommended dose in Japanese patients with advanced solid tumors. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients.
The role of tumor-associated macrophages (TAMs) in cancer is often correlated with poor prognosis, even though this statement should be interpreted with care, as the effects of macrophages primarily depend on their localization within the tumor. This versatile cell type orchestrates a broad spectrum of biological functions and exerts very complex and even opposing functions on cell death, immune stimulation or suppression, and angiogenesis, resulting in an overall pro- or antitumoral effect. We are only beginning to understand the environmental cues that contribute to transient retention of macrophages in a specific phenotype. It has become clear that hypoxia shapes and induces specific macrophage phenotypes that serve tumor malignancy, as hypoxia promotes immune evasion, angiogenesis, tumor cell survival, and metastatic dissemination. Additionally, TAMs in the hypoxic niches within the tumor are known to mediate resistance to several anticancer treatments and to promote cancer relapse. Thus, a careful characterization and understanding of this macrophage differentiation state is needed in order to efficiently tailor cancer therapy.
Resistance to chemotherapy remains a major impediment to the management of most types of cancer. Both intrinsic and acquired drug resistance are mediated by several cellular and molecular mechanisms, including alternative growth-signaling pathways unaffected by specific therapies, alterations in the tumor microenvironment (e.g., hypoxia and angiogenesis), and active transport of drugs out of the cell. Epidemiological studies have validated an inverse correlation between the consumption of dietary polyphenols and the risk of cancer, which has been attributed to polyphenol antioxidant capacity and their potential to inhibit activation of procarcinogens, cancer cell proliferation, metastasis, and angiogenesis, and inhibition or downregulation of active drug efflux transporters. Moreover, polyphenols can induce apoptosis in cancer cells and modulate immune responses and inflammatory cascades. Augmentation of the efficacy of chemotherapy and prevention of multidrug resistance are other important effects of dietary polyphenols that deserve further research, especially after the discovery of tight “crosstalk” between aberrant growth signaling and metabolic dysfunction in cancer cells. In this review, we cover what is currently known about the role of natural polyphenolic compounds in overcoming cancer drug resistance mediated by diverse primary and secondary resistance mechanisms.
The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).
Introduction:
Trabectedin, a marine-derived DNA-binding antineoplastic agent, has been registered by the EMA and recently also by the FDA for the treatment of patients with advanced soft-tissue sarcoma (STS), a rare and heterogeneous disease.
Areas covered:
The antitumor activity of trabectedin is related both to direct effects on cancer cells, such as growth inhibition, cell death and differentiation, and indirect effects related to its anti-inflammatory and anti-angiogenic properties. Furthermore, trabectedin is the first compound that targets an oncogenic transcription factor with high selectivity in mixoid liposarcomas. This peculiar mechanism of action is the basis of its clinical development. The clinical pharmacology of trabectedin, the subsequent phase I, II and III trials are summarized and put into perspectives in this review.
Expert opinion:
Trabectedin is a relevant pleiotropic antitumoral agent within the complex scenario of the management of STS. It can be used in advanced STS, either after failure of anthracyclines and ifosfamide or in patients unfit for these drugs, especially when reaching a high-tumor control and a long-term benefit is a priority. Toxicity profile is acceptable and manageable with no reported cumulative toxicities. Therefore, trabectedin has become one relevant therapeutic option in metastatic STS, especially in selected histologies.
Angiogenesis, or new blood vessel formation, is an important process in the pathogenesis of several diseases and thus has been targeted for the prevention and treatment for many disorders. However, the anti-angiogenic agents that are currently in use are mainly synthetic compounds and humanized monoclonal antibodies, which are either expensive or toxic, thereby limiting their use in many patients. Therefore, it is necessary to identify less toxic, inexpensive, novel and effective anti-angiogenic molecules. Several studies have indicated that natural plant products can meet these criteria. In this review, we discuss the anti-angiogenic properties of natural compounds isolated from plants and the molecular mechanisms by which these molecules act. Finally, we summarize the advantages of using plant products as anti-angiogenic agents. Compared with currently available anti-angiogenic drugs, plant products may not only have similar therapeutic potential but are also inexpensive, less toxic, and easy to administer. However, novel and effective strategies are necessary to improve their bioavailability for clinical use.
Angiogenesis is indispensible for tumor growth and metastasis. Antiangiogenic therapy is now a validated major strategy in cancer clinic; several small molecule angiogenic inhibitors have been successfully translated into clinic for multiple cancer indications. In the past decade, many natural products with potent antiangiogenic activity were explored and the underlying molecular mechanisms were revealed. One important mechanism is the inhibition of one or several steps in VEGF/VFGFR signaling pathway. Other factors (bFGF, HIF-1α, NF-κB etc.) capable of regulating angiogenesis, are also down-regulated by some natural products. Moreover, some of the antiangiogenic natural products also significantly inhibit vasculogenic mimicry (VM), another important vessel recruitment avenue in cancer, by regulating the key signaling of VM formation including VE-cadherin, EphA2, and Nodal signaling. In this mini-review, we summarized the natural products with suppressive effect on tumor angiogenesis and VM according to their diverse molecular mechanisms, and discussed the major direction of future research in this field.
Acute leukemia is a malignant clonal hematopoietic stem cell disease. In the current study, we examined the effects of bryostatin 5 on acute monocytic leukemia cells in vitro and in vivo. We also explored the mechanisms and pathways underlying the increase in apoptosis induced by bryostatin 5. Bryostatin 5 inhibited the growth of primary acute monocytic leukemia cells and U937 cells in a dose- and time-dependent manner. Bryostatin 5 also induced an increase in apoptosis and a decrease in the mitochondrial membrane potential (MMP) in U937 cells. Transmission electron microscopy (TEM) revealed that bryostatin 5-treated cells displayed typical apoptotic characteristics (chromatin condensation, karyopyknosis and formation of crescents and apoptotic bodies). In addition, bryostatin 5 increased the expression of P53 upregulated modulator of apoptosis (PUMA) and slightly increased P53 expression. Bryostatin 5 also significantly decreased Bcl-XL expression and significantly increased the expression levels of Bak, Bax, cleaved caspase 9 and cleaved caspase 3. The pro-apoptotic activity of bryostatin 5 in U937 cells was inhibited by PUMA siRNA and z-LEHD-fmk (a specific caspase 9 inhibitor). In addition, the PUMA siRNA significantly affected the expression of cleaved caspase 9, whereas z-LEHD-fmk had little effect on the expression of PUMA. The results suggest that PUMA is located upstream of caspase 9 in this apoptotic signaling pathway. These novel findings provide mechanistic insight into the induction of apoptosis by bryostatin 5 and might facilitate the development of clinical strategies to enhance the therapeutic efficacy of treatments for acute monocytic leukemia.
13074
Background: AVE8062 is a synthetic, water-soluble compound, analog of Combretastatin A4, currently in Phase I clinical trials. It inhibits tubulin polymerization through binding to the colchicine site of tubulin. In vivo, it induces rapid tumor blood flow shutdown and necrosis, leading to tumor regressions (Proc AACR, 2002). Previously (Proc AACR, 2003), we reported a high synergy resulting from the combination of AVE8062 with either cisplatin or carboplatin in a preclinical in vivo model. We report here the combination data of AVE8062 with oxaliplatin. Methods: A 3-arm dose-response study was performed comparing the single agents and their combination. Synergy was defined as a log cell kill (lck) of at least 1 log superior to the lck of the best single agent. The AVE8062 / oxaliplatin simultaneous combination was evaluated in female BALB/c mice bearing advanced stage (250mg) SC murine colon C51 adenocarcinoma. Drugs were administered IV with 2 intermittent injections, 4 days apart. The combination arm was evaluated over 7 dose levels. Results: At the Highest nontoxic dose (HNTD - 58 mg/kg/inj), AVE8062 was found active: 0.9 lck, 1/5 partial regression (PR) and no complete regression (CR). At the HNTD (7 mg/kg/inj), oxaliplatin was found highly active [5.8 lck, 5/5 CR, no tumor free survivors (TFS)]. The HNTD for the combination (58 mg/kg/inj of AVE8062 with 7 mg/kg/inj of oxaliplatin) was well tolerated with 11.7% body weight loss at nadir. The combination was highly active over the 2 highest dose levels with TFS on day 148 post tumor implantation (4/6 TFS at combination HNTD and 6/6 TFS at 80% HNTD). A high antitumor activity was maintained at 60% HNTD (5.9 lck, 6/6 CR and no TFS). The lowest dose tested, corresponding to 1/10 of the HNTD fractions, was found active with a lck of 1.0 and no regression. Conclusions: The combination of AVE8062 with oxaliplatin was found highly synergistic (superior activity than either of the single agents alone). The combination was well tolerated with a combination toxicity index of 2, indicating that there was no overlap in host toxicity. These data provide a good rationale to perform Phase I combination trials combining AVE8062 with oxaliplatin.
[Table: see text]
This book covers the latest developments in the therapeutic implications of angiogenesis, ranging from angiogenesis in the brain, angiogenesis in cancer, angiogenesis’ role in atherosclerosis and heart disease as well as metabolic disorders and peripheral vascular disease. The book is comprehensive in its coverage of angiogenesis in a diverse set of diseases and examines the role of cellular and subcellular structures during the development of angiogenesis. Well-organized and thorough, this is an ideal book for researchers and biomedical engineers working in the field of therapeutic implications of angiogenesis.
This book also:
Covers the basics of the physiology of angiogenesis, including VEGF pathways in angiogenesis, integrins in angiogenesis, angiogenesis and exercise physiology, and more
Details the role of angiogenesis in atherosclerosis and heart disease, including vascular endothelial growth factor and atherosclerotic plaque progression
as well as angiogenesis and heart failure
Illustrates in detail brain angiogenesis after stroke and the relationship between angiogenesis and Alzheimer's disease
Most metastasizing tumor cells reach distant sites by entering the circulatory system. Within the bloodstream, they are exposed to severe stress due to loss of adhesion to extracellular matrix, hemodynamic shear forces, and attacks of the immune system, and only a few cells manage to extravasate and to form metastases. We review the current understanding of the cellular and molecular mechanisms that allow tumor cells to survive in the intravascular environment and that mediate and promote tumor cell extravasation. As these processes are critical for the metastatic spread of tumor cells, we discuss implications for potential therapeutic approaches and future research. Most metastasizing tumor cells reach distant sites by entering the circulatory system. Within the bloodstream, they are exposed to severe stress due to loss of adhesion to extracellular matrix, hemodynamic shear forces, and attacks of the immune system, and only a few cells manage to extravasate and to form metastases. We review the current understanding of the cellular and molecular mechanisms that allow tumor cells to survive in the intravascular environment and that mediate and promote tumor cell extravasation. As these processes are critical for the metastatic spread of tumor cells, we discuss implications for potential therapeutic approaches and future research.
The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells.
Purpose:
In 2012, due to a shortage of pegylated liposomal doxorubicin, single agent trabectedin was proposed as an alternative of treatment to our patients with recurrent ovarian cancer (ROC) at our center. The aim of this retrospective study was to evaluate efficacy and tolerability of trabectedin in this context.
Patients and methods:
This retrospective study included all patients who received intravenous trabectedin 1.3mg/m(2) over 3h every 3weeks for ROC between January 2012 and December 2015 at the Centre hospitalier de l'Université de Montreal. The primary outcome was the progression-free survival (PFS) based on CA-125 levels, clinical exam and/or Response Evaluation Criteria in Solid Tumors criteria. We also evaluated overall survival (OS), response rate and toxicities.
Results:
A total of 42 patients with a median age of 59years received trabectedin in 2nd or 3rd line (12% of patients), 4th or 5th line (43%), and ≥6 lines (45%) and 45% were platinum-resistant. The median number of cycles received was 6 (range 1-19cycles). Complete response (CR), partial response (PR), stable disease (SD) and progression occurred in 19%, 29%, 33% and 19% of patients, respectively. The median PFS and OS was 4.3months (95% CI, 3.4-5.1) and 16.2months (95% CI, 9.0-23.5), respectively. In patients with a clinical benefit (CR, PR, SD), the median PFS was 4.6months. Trabectedin was well tolerated with few adverse events.
Conclusion:
Our results demonstrate that trabectedin has an interesting efficacy as a single agent in heavily treated ROC patients.
The search for small molecule inhibitors has gained prominence with the recognition of their inherent advantage for cancer therapy. Combretastatin is a naturally occurring small stilbenoid. By virtue of the ability to bind to tubulin combretastatin and its derivatives promote depolymerisation of microtubules as well as inhibit tubulin polymerisation. This suppresses cell proliferation signalling and induces apoptosis. Combretastatins activate mitotic checkpoints that lead to mitotic catastrophe and apoptosis. They subvert the signalling systems which stimulate invasion, activate EMT (epithelial mesenchyme transition) activation and promote tumour progression. Allied with the ability to suppress angiogenesis these compounds have been viewed as potential inhibitors of metastasis.
The notion of merging RTK (receptor tyrosine kinase) inhibition with suppression of invasion and possible inhibition of EMT has contributed to the credibility of combretastatins as anti-cancer agents. Invaluable are their attributes of inhibiting tumour growth and induction of apoptosis and necrosis by reducing blood supply to the tumour. Aside from these biological effects, this commentary also discusses the issues of the targeting of combretastatins to the tumour vasculature and effective delivery of the drugs encapsulated in nanospheres. Notwithstanding the perceived benefits, one can see a compelling need to understand the effects of combretastatin on the actin cytoskeletal dynamics and the disruption of microtubule polymerisation, and whether it is more efficient a tumour inhibitor than the conventional drugs that target microtubule dynamics. Combinations of combretastatins with other vascular disrupting agents have been attempted. It is essential to establish the perceived inhibition of EMT beyond reasonable doubt. This might justify using the combretastatins with allosteric EMT and Akt inhibitors as additional choices for pre-clinical/clinical studies.
Introduction of cART in 1996 has drastically increased the life expectancy of people living with HIV-1. However, this treatment has not allowed cure as cessation of cART is associated with a rapid viral rebound. The main barrier to the eradication of the virus is related to the persistence of latent HIV reservoirs. Evidence is now accumulating that purging the HIV-1 reservoir might lead to a cure or a remission. The most studied strategy is the so called “shock and kill” therapy. This strategy is based on reactivation of dormant viruses from the latently-infected reservoirs (the shock) followed by the eradication of the reservoirs (the kill). This review focuses mainly on the recent advances made in the “shock and kill” therapy. We believe that a cure or a remission will come from combinatorial approaches i.e. combination of drugs to reactivate the dormant virus from all the reservoirs including the one located in sanctuaries, and combination of strategies boosting the immune system. Alternative strategies based on cell and gene therapy or based in inducing deep latency, which are evoked in this review reinforce the idea that at least a remission is attainable.
Marine organisms are an important source of antitumor active substances. Thus, pharmaceutical research in recent years has focused on exploring new antitumor drugs derived from marine organisms, and, many peptide drugs with strong antitumor activities have been successfully extracted. Based on different mechanisms, this paper reviews the research on several typical antitumor bioactive peptides in marine drugs and the latest progress therein. Additionally, the development prospects for these antitumor bioactive peptide-based drugs are discussed so as to provide a reference for future research in this field. This article is protected by copyright. All rights reserved.
The tumor vasculature transports oxygen, nutrients and drugs for crucial roles in tumor therapy. Antivascular therapy directly targets existing tumor vessels to reduce blood perfusion and then inhibit tumor growth. Vascular disrupting agents and ultrasound-stimulated microbubble destruction use chemical toxicity and physical effect, respectively, to damage vascular endothelial cells for antivascular therapy. Moreover, antivascular therapy can break vessel wall barriers and change the tumor microenvironment to compensate for the limitations of conventional chemotherapy or radiotherapy. This review presents current progress and an overview of antivascular therapy, which can inform the development and application in cancer research.
Therapy resistance is a major challenge in the management of ovarian cancer (OC). Advances in detection and new technology validation have led to the emergence of biomarkers that can predict responses to available therapies. It is important to identify predictive biomarkers to select resistant and sensitive patients in order to reduce important toxicities, to reduce costs and to increase survival. The discovery of predictive and prognostic biomarkers for monitoring therapy is a developing field and provides promising perspectives in the era of personalized medicine. This review article will discuss the biology of OC with a focus on targetable pathways; current therapies ; mechanisms of resistance; predictive biomarkers for chemotherapy, antiangiogenic and DNA-targeted therapies, and optimal cytoreductive surgery; and the emergence of liquid biopsy using recent studies from the Medline database and ClinicalTrials.gov.
The development of new anticancer drugs has strongly contributed to improve patients’ outcomes. However, the question can be raised whether the sometimes minor benefits are worth the cost to both the individuals and the society. The aim of this medico-economic study was to evaluate trabectedin cost-effectiveness compared with end-stage care in the treatment of soft-tissue sarcoma. We retrospectively analysed data from 45 patients treated with trabectedin for soft tissue sarcoma. Real-life data of clinical benefits and costs of trabectedin were compared with simulated end-stage treatment. Univariate and probabilistic sensitivity analyses identified key drivers of the incremental cost-effectiveness ratio. Trabectedin was associated with longer progression-free survival (4.0 months versus 1.6 months) and higher costs (€24,780 versus €15,490) compared with end-stage treatment. The incremental cost per year of progression-free survival gained with trabectedin was €46,104 (95% confidence interval; €45,039 − €47,169). The results were relatively insensitive to changes. Trabectedin was cost-effective in the context of an orphan disease, when used to treat patients with a short life expectancy and few therapeutic options.
The formation of new blood vessels plays a crucial for the development and progression of pathophysiological changes associated with a variety of disorders, including carcinogenesis. Angiogenesis inhibitors (anti-angiogenics) are an important part of treatment for some types of cancer. Some natural products isolated from marine invertebrates have revealed antiangiogenic activities, which are diverse in structure and mechanisms of action. Many preclinical studies have generated new models for further modification and optimization of anti-angiogenic substances, and new information for mechanistic studies and new anti-cancer drug candidates for clinical practice. Moreover, in the last decade it has become apparent that galectins are important regulators of tumor angiogenesis, as well as microRNA. MicroRNAs have been validated to modulate endothelial cell migration or endothelial tube organization.
In the present review we summarize the current knowledge regarding the role of marine-derived natural products, galectins and microRNAs in tumor angiogenesis.
All organs consist of an epithelium and an associated mesenchyme, so these epithelial-mesenchymal intercations are among the most important phenomena in nature. The aim of this article is the summarize the common mechanisms involved in the establishment of epithelial mesenchymal transition in three biological processes, namely organogenesis, tumor progression and metastasis, and angiogenesis, apparently independent each from other. A common feature of these processes is the fact that specialized epithelial cells lose their features, including cell adhesion and polarity, reorganize their cytoskeleton, and acquire a mesenchymal morphology and the ability to migrate.
Introduction:
The majority of women with epithelial ovarian cancer present with advanced stage disease and there is a critical need for novel drugs and treatment strategies to improve outcomes. Trabectedin is a unique cytotoxic agent with a complex mechanism of action. It binds to guanines in the N2 position in the minor groove of DNA and its cytotoxicity involves DNA repair pathways and transcription regulation. Trabectedin's activity is also related to the drug-induced changes of the tumor microenvironment. It has been shown to improve progression-free survival in combination with pegylated liposomal doxorubicin in patients with platinum-sensitive relapsed ovarian cancer. The most common adverse events experienced with trabectedin are nausea, vomiting, fatigue, neutropenia and transaminitis. Studies of biomarkers that are predictors of trabectedin benefit are underway. Areas covered: This review covers trabectedin's mechanism of action and pharmacology, the clinical development of the drug in ovarian cancer, ongoing trials, and the use of biomarkers to predict efficacy to trabectedin. Expert opinion: Ongoing phase III trials with biomarker studies will help to elucidate the patient population that will best benefit from trabectedin and pave the way for personalized treatment decisions and potential future approval of trabectedin in the United States.
Single mechanism based anti-angiogenesis agents have, much like other anti-angiogenic strategies, been shown to have modest or no effect on metastasis when given in combination with chemotherapy. The VEGF-A monoclonal antibody, bevacizumab, is one such single mechanism agent. In 2011, the FDA removed the bevacizumab indication for metastatic breast cancer treatment because of the lack of evidence for achievement of improved overall survival. This experience emphasizes the need for broad spectrum anti-angiogenesis therapy that may act alone or in combination with standard chemotherapy. Tyrosine kinase inhibitor (TKI) agents are examples of agents that affect the activity of more than one cell surface vascular growth factor receptor. In this chapter, we review the inventory of available anti-angiogenesis therapies, endogenous factors in tumors that defend the lesions against anti-angiogenic drug interventions and the prospects for development of new anti-angiogenesis drugs with multiple actions that are suitable for use with standard chemotherapeutic agents. Additionally, we examine possible nanoparticle-targeted delivery of chemotherapeutic agents directed at pathological angiogenesis. Such agents may have increased efficacy and, because of localized action, may exhibit increased safety.
Polyphenols can be found in natural products of plant origin, including vegetables, fruits and beverages. A large number of these plant origin compounds are an integral part of the human diet, and in the past decade evidence have shown their beneficial properties in human health, by acting in several cell signaling pathways. Among other beneficial effects, polyphenols have been associated with angiogenesis. Increasing evidence highlighting the ability of dietary polyphenols to influence angiogenesis by interfering with multiple signaling pathways is debated. Particular emphasis is given to the mechanisms that ultimately may induce the formation of capillary-like structures (by increasing endothelial cell proliferation, migration, and invasion) or, conversely, may inhibit the steps of angiogenesis leading to the inhibition/regress of vascular development. Dietary polyphenols can, therefore, be viewed as promising nutraceuticals but important aspects have still to be further investigated, to deep knowledge concerning their concentration-mediated effects, effect of specific polyphenols, and respective metabolites, to ensure their appropriate and effective usefulness as proangiogenic or antiangiogenic nutraceuticals. This article is protected by copyright. All rights reserved.
Angiogenesis has become an attractive target for cancer therapy since the US Food and Drug Administration (FDA) approved the first angiogenesis inhibitor (bevacizumab) for the treatment of metastatic colorectal cancer in 2004. In following years, a large number of angiogenesis inhibitors have been discovered and developed, ranging from monoclonal antibodies, endogenous peptides, to small organic molecules and microRNAs. Many of them are now entering the clinical trial, or achieving approval for clinical use. However, major limitations have been observed about angiogenesis inhibitors by continued clinical investigations, such as resistance, enhancing tumor hypoxia and reducing delivery of chemotherapeutic agents, which might be the main reason for poor improvement in overall survival after angiogenesis inhibitor administration in clinic. Therefore, optimal anti-angiogenic therapy strategies become critical. The present review summarizes recent researches in angiogenesis inhibitors, and proposes a perspective on future directions in this field.
The process of angiogenesis is quite well-known nowadays. Some medicines and extracts affecting this process are already used routinely in supporting the conventional treatment of many diseases that are considered angiogenic such as cancer. However, we must be aware that the area of currently used drugs of this type is much narrower than the theoretical possibilities existing in therapeutic angiogenesis. Plant substances are a large and diverse group of compounds that are found naturally in fruits, vegetables, spices, and medicinal plants. They also have different anticancer properties. The aim of this literature review article is to present the current state of knowledge concerning the molecular targets of tumor angiogenesis and the active substances (polyphenols, alkaloids, phytohormones, carbohydrates, and terpenes) derived from natural sources, whose activity against cancer angiogenesis has been confirmed.
Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin has a unique multi-faceted mechanism of action that involves transcription regulation and DNA repair systems, including transcription-coupled nucleotide excision repair and homologous recombination repair (HRR) as the main hallmarks of its antiproliferative activity. In addition, trabectedin has shown the ability to modulate the tumor microenvironment. Indeed, the activity of trabectedin is related to altered function and expression of DNA repair genes, such as BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2. The particular sensitivity of sarcoma, ovarian and breast cancer cells deficient in HRR, previously observed in preclinical models, now has been confirmed in the clinical setting as well, suggesting that BRCA mutations are associated with improved clinical responses to trabectedin. Current efforts are focused on the evaluation of these unique features of trabectedin and on the identification of predictive factors for patients with an objective to determine whether a deficiency of HRR DNA repair pathway could impact the clinical benefit achieved from trabectedin.
Introduction: Trabectedin (ET-743) is a synthetic marine derived alkylating agent, extracted originally from a Caribbean Sea sponge. It is approved for the treatment of Soft Tissue sarcomas (STS) in Europe and recently by the FDA for liposarcomas and leiomyosarcomas.
Areas Covered: Trabectedin has multiple mechanisms of action, including one targeting the FUS-CHOP oncogene in Myxoid/Round cell Liposarcomas. Numerous Phase I, II and III clinical trials have been conducted with Trabectedin. It has been studied as monotherapy or in combination with other chemotherapeutic agents. The recommended dose based on clinical trials is 1.5 milligrams/m² continuous infusion over 24 hours once every 3 weeks for STS with evidence of disease control in multiple clinical trials at this dose. The most common Grade 3/4 toxicities include neutropenia and transient noncumulative elevations of ALT and AST. Steroid pretreatment has shown efficacy in reducing liver and bone marrow toxicity. In phase III testing comparing trabectedin to dacarbazine, trabectedin was associated with a significantly improved progression free survival rate in patients with advanced lipo- and leiomyosarcomas.
Expert Opinion: Trabectedin is an important new addition to the limited treatment options currently available for STS, especially for patients with liposarcoma that have progressed on standard chemotherapeutic regimens.
Vinca alkaloids have been approved as anti-cancer drugs for more than 50 years. They have been classified as cytotoxic chemotherapy drugs that act during cellular mitosis, enabling them to target fast growing cancer cells. With the evolution of cancer drug development there has been a shift towards new “targeted” therapies to avoid the side effects and general toxicities of “cytotoxic chemotherapies” such as the vinca alkaloids. Due to their original classification, many have overlooked the fact that vinca alkaloids, taxanes and related drugs do have a specific molecular target: tubulin. They continue to be some of the most effective anti-cancer drugs, perhaps because their actions upon the microtubule network extend far beyond the ability to halt cells in mitosis, and include the induction of apoptosis at all phases of the cell cycle. In this review, we highlight the numerous cellular consequences of disrupting microtubule dynamics, expanding the textbook knowledge of microtubule destabilizing agents, and providing novel opportunities for their use in cancer therapy.
The formation of blood capillaries to sustain development and growth of new tissues is referred to as angiogenesis. Angiogenesis is pivotal in both carcinogenesis and metastasis since capillaries are the sole source of supplying nutrients and oxygen to the proliferating tumor cells; therefore, this dependency of tumor growth on angiogenesis challenges researchers to halt tumor growth by targeting angiogenesis with the help of either synthetic or natural inhibitors. Many synthetic inhibitors of angiogenesis have not only come into force but also resulted in some severe adverse effects. Natural compounds may effectively fit into this condition and possibly decrease the time of treatment. In the recent past, literature is replete with evidences advocating the usefulness of natural compounds that target multiple biochemical pathways. The additional advantage of natural compounds is that their active principles interact with one another and work synergistically to give more meaningful and reliable effects than individual principle. Hence, if we are somehow able to combine more than two natural compounds, then it may be possible to enhance their potential by many folds, which shall prove to be very effective in combating tumor angiogenesis. This review shall discuss the concept of angiogenesis, molecular pathways, and angiogenic inhibitors and their specific targets and potential of natural compounds to greatly enhance the current knowledge of angiogenesis-inhibiting factors.
This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab in advanced cancer patients. Thirteen patients were enrolled and treated with plitidepsin at three dose levels (2.8 mg/m, n=3; 3.8 mg/m, n=4; and 4.8 mg/m, n=6) with a fixed dose of bevacizumab (10 mg/kg). Both agents were administered intravenously at D1 and D15 of a 28-day cycle. All 13 patients were evaluable for safety and toxicity. Dose-limiting toxicities occurred in two out of six patients treated at the maximum dose tested (plitidepsin 4.8 mg/m and bevacizumab 10 mg/kg) and consisted of grade 3 fatigue, grade 3 myalgia, and two grade 2/3 alanine aminotransferase increases lasting for more than 7 days or leading to subsequent cycle delay greater than 2 weeks (n=1 each). The recommended dose for the combination of plitidepsin with bevacizumab was 3.8 mg/m for plitidepsin and 10 mg/kg for bevacizumab every 2 weeks. Most frequent treatment-related adverse events were nausea, vomiting, fatigue, epistaxis, and headache. Relevant hematological toxicity was minimal. Objective disease responses were not observed; however, stable disease (>3 months) was observed in four patients with colorectal cancer, renal cancer, and cervical cancer. Combining plitidepsin with bevacizumab combination is feasible. Stable disease was the best response obtained.
For the first time combretastatins were isolated from African willow tree Combretum Caffrum. Subsequent studies have shown the impact of combretastatin A4 phosphate, a water-soluble prodrug, on endothelial cells in tumor vascular system. The same effect was not observed in the vascular system. This selectivity is associated with combretastatins mechanism of action: binding to colchicine domain of microtubules, which affects the cytoskeleton functionality of immature endothelial cells. At the same time, combretastatins directly induce cell death via apoptosis and/or mitotic catastrophe pathways. The combination of both elements makes combretastatin an anticancer compound of high efficiency.
Introduction:
The active clinical research programme of trabectedin continues to improve knowledge on the therapeutic activity and toxicity of the drug in the treatment of soft tissue sarcomas (STS). In contrast, limited number of data is available on its use outside of clinical trials.
Patients and methods:
We retrospectively analysed efficacy and safety of trabectedin when given in daily practice to patients with advanced/recurrent STS. Outcomes were compared with previously published works including clinical and retrospective studies.
Results:
Forty-five patients received trabectedin between January 2005 and May 2014. Sarcomas were histologically heterogeneous in our cohort (37.9% of other types of sarcomas than L-sarcomas). Our patients had poor baseline health status (ECOG ≥ 2 [17.8%]) and had received multiple previous lines of chemotherapy. Patients received a median of five cycles of treatment (1-22). The objective response rate was statistically superior in our study (37.8%) compared to the other works. However, median PFS was similar. Trabectedin-related serious adverse events (AEs) induced hospitalizations and treatment discontinuation in 22 and 15% of patients.
Conclusion:
This analysis confirms the efficacy of trabectedin in clinical practice (with a third of patients experiencing prolonged disease control) and highlighted the importance of its administration as early line therapy to allow the best management of serious AEs.
Purpose:
Doxorubicin and trabectedin are considered active drugs in soft tissue sarcoma (STS). The combination of both drugs was hypothesized to be advantageous and safe on the basis of preclinical evidence and a previous phase I trial, respectively. The aim of this study was to compare the clinical outcome of trabectedin plus doxorubicin with doxorubicin as first-line treatment of advanced STS patients.
Patients and methods:
In this open-label randomized phase II trial, the main end point was progression-free survival (PFS). Trabectedin 1.1 mg/m(2) in a 3-hour infusion plus doxorubicin 60 mg/m(2) as the experimental arm and doxorubicin 75 mg/m(2) as the control arm were administered for up to six cycles. Translational research was planned to correlate the expression of apoptotic and DNA repair genes with clinical outcome.
Results:
In 115 randomly assigned patients, the median PFS was 5.5 months in the control arm and 5.7 months in the experimental arm (hazard ratio, 1.16; 95% CI, 0.79 to 1.71; P = .45) in the intent-to-treat analysis. The trial was stopped for futility after the interim analysis, because the results in the experimental arm showed the risk reduction for the main end point to be < 9.64%. The proportion of patients with grade 3 or 4 thrombocytopenia, asthenia, and liver toxicity was significantly higher in the experimental arm. FAS and p53 were shown to be prognostic factors for PFS (7.0 months if FAS+ and p53-; 3.4 months if FAS+/p53+ or FAS-/p53-; and 0.7 months if FAS- and p53+; P < .001) and for overall survival.
Conclusion:
Trabectedin plus doxorubicin did not show superiority over doxorubicin alone as first-line treatment of advanced STS. The prognostic role of apoptotic key genes, FAS and p53, was shown to be robust enough to continue this research line.
Background:
Preclinical and clinical data suggest that xeroderma pigmentosum G gene (XPG) status might predict trabectedin efficacy. This phase 2 study evaluated the efficacy of trabectedin at a dose of 1.3 mg/m(2) as a 3-hour intravenous infusion every 3 weeks in hormone receptor-positive, HER-2 (human epidermal growth factor receptor 2)-negative, advanced breast cancer patients according to the tumor level of XPG mRNA expression.
Patients and methods:
Patients were stratified into high-XPG (>3) or low-XPG (≤ 3) groups. The primary efficacy end point was progression-free survival (PFS) rate at 16 weeks (PFS4); secondary efficacy end points were overall response rate (ORR), duration of response, PFS, overall survival, and safety of trabectedin in this patient population.
Results:
Forty-four patients were treated, 21 with high XPG and 23 with low XPG. Four high-XPG and 6 low-XPG patients experienced PFS4; the criterion for further recruitment (> 6 patients experienced PFS4) was thus not met, and recruitment was stopped. One high-XPG patient had a partial response (ORR, 5%). One low-XPG patient had a complete response, and 2 low-XPG patients had partial responses (ORR, 13%). Comparison of efficacy parameters between high-XPG and low-XPG patients showed no statistically significant differences. ORR in the efficacy population was 9.3%, median PFS was 1.9 months, and overall survival was 11.8 months. The safety of trabectedin in breast carcinoma was similar to that shown in other indications.
Conclusion:
Trabectedin as single agent had limited activity in hormone-positive, HER-2-negative advanced breast cancer. XPG mRNA expression was not predictive of trabectedin efficacy.
Natural products and their molecular frameworks have a long tradition as valuable starting points for medicinal chemistry and drug discovery. Recently, there has been a revitalization of interest in the inclusion of these chemotypes in compound collections for screening and achieving selective target modulation. Here we discuss natural-product-inspired drug discovery with a focus on recent advances in the design of synthetically tractable small molecules that mimic nature's chemistry. We highlight the potential of innovative computational tools in processing structurally complex natural products to predict their macromolecular targets and attempt to forecast the role that natural-product-derived fragments and fragment-like natural products will play in next-generation drug discovery.
Chemotherapy is the standard treatment for many, if not all, metastatic cancers. While chemotherapy is often capable of inducing cell death in tumors leading to shrinkage of the tumor bulk, many patients suffer from recurrence and ultimately death due to resistance. During the last decade, treatment resistance has attracted great attention followed by some seminal discoveries, including sequential mutations, cancer stem cells, and bidirectional inter-conversion of stem and non-stem cancer cell populations. Nevertheless, the successful treatment of cancer will require a considerable refinement of our knowledge concerning treatment resistance. In doing so, we expect that a more informed and refined approach to treat cancer will be developed and this may improve prognosis of cancer patients. In this review, we will discuss the current knowledge concerning the failure of cancer treatments and the potential approaches to overcome therapeutic resistance.
Vascular-disrupting agents (VDAs) are a new class of compounds that target tumor vasculature, causing a rapid and acute collapse of the blood vessel network surrounding the tumor, slowing blood flow and ultimately resulting in tumor necrosis. Plinabulin is a small-molecule VDA that works by selectively binding to the colchicine binding site of endothelial tubulin, leading to disorganization of the endothelial cytoskeleton and inhibition of tumor blood flow. Clinical studies have shown that plinabulin markedly reduces tumor blood flow, providing significant clinical benefit to patients with solid tumors. Further results in patients with non-small cell lung cancer (NSCLC) demonstrated that plinabulin enhanced the antitumor activity of docetaxel, with a favorable safety profile. Plinabulin is currently undergoing phase I clinical studies as monotherapy for the treatment of solid tumors and lymphoma and phase II evaluation in combination with docetaxel for the treatment of NSCLC.
Traditionally, site of disease and anatomic staging have been used to define patient populations to be studied in individual cancer clinical trials. In the past decade, however, oncology has become increasingly understood on a cellular and molecular level, with many cancer subtypes being described as a function of biomarkers or tumor genetic mutations. With these changes in the science of oncology have come changes to the way we design and perform clinical trials. Increasingly common are trials tailored to detect enhanced efficacy in a patient subpopulation, e.g., patients with a known biomarker value or whose tumors harbor a specific genetic mutation. Here, we provide an overview of traditional and newer biomarker-based trial designs, and highlight lessons learned through implementation of several ongoing and recently completed trials.
Angiogenesis is a process essential for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown only moderately improved results and is beset with practical limitations, despite theoretical therapeutic advantages. Inevitably resistance develops, through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions, with more invasive phenotypes. Antiangiogenic-targeted therapies may find improved efficacy in combination therapies; with others in this class, that directly or indirectly target separate pathways or different components of the same pathway, or with a separate class of tumor vasculature-disrupting agents. This review discusses the challenges and strategies for optimization of combination therapies including metronomic administration of drugs and the need for suitable prognostic and surrogate response biomarkers.