[Show abstract][Hide abstract] ABSTRACT: Recent therapeutic advances in oncology have been driven by the identification of tumour genotype variations between patients, called interpatient heterogeneity, that predict the response of patients to targeted treatments. Subpopulations of cancer cells with unique genomes in the same patient may exist across different geographical regions of a tumour or evolve over time, called intratumour heterogeneity. Sequencing technologies can be used to characterize intratumour heterogeneity at diagnosis, monitor clonal dynamics during treatment and identify the emergence of clinical resistance during disease progression. Genetic interpatient and intratumour heterogeneity can pose challenges for the design of clinical trials that use these data.
[Show abstract][Hide abstract] ABSTRACT: Background:The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a γ-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor.Methods:Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping.Results:In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure.Conclusion:RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy.British Journal of Cancer advance online publication, 18 July 2013; doi:10.1038/bjc.2013.380 www.bjcancer.com.
British Journal of Cancer 07/2013; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background To determine the recommended phase II dose (RP2D) and assess the safety, pharmacokinetics (PKs) and pharmacodynamics of RO4929097in combination with temsirolimus. Methods Escalating doses of RO4929097 and temsirolimus were administered at three dose levels. Patients received once daily oral RO4929097 on a 3 days on/4 days off schedule every week, and weekly intravenous temsirolimus. Blood samples were collected for PK analysis. Archival tissue specimens were collected for Notch pathway biomarker analysis and genotyping of frequent oncogenic mutations. Results Seventeen patients with refractory advanced solid tumors were enrolled in three dose levels (DLs): DL1 (RO4929097 10 mg; Temsirolimus 25 mg), DL2 (RO4929097 20 mg; Temsirolimus 25 mg), and DL3 (RO4929097 20 mg; Temsirolimus 37.5 mg). The most common toxicities related to the study drug combination included: fatigue (82 %; grade 3 6 %), mucositis, (71 %; grade 3 6 %), neutropenia (59 %; grade 3 12 %), anemia (59 %; grade 3 0 %), and hypertriglyceridemia (59 %; grade 3 0 %). Two dose-limiting toxicities, grade 3 rash and grade 3 mucositis, were observed in the same patient in the first dose level prompting dose expansion. Eleven patients (73 %) had stable disease as their best response. Co-administration of RO4929097 was associated with increased clearance and reduced exposure to temsirolimus, suggestive of drug-drug interaction via CYP3A4 induction. No correlation between the expression of Notch pathway biomarkers or genotype and time to progression was noted. Conclusions RO4929097 can be safely combined with temsirolimus in patients with advanced solid tumors. The RP2D was established at 20 mg of RO4929097 combined with 37.5 mg of temsirolimus.
Investigational New Drugs 07/2013; · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Developments in genomics, including next-generation sequencing technologies, are expected to enable a more personalized approach to clinical care, with improved risk stratification and treatment selection. In oncology, personalized medicine is particularly advanced and increasingly used to identify oncogenic variants in tumor tissue that predict responsiveness to specific drugs. Yet, the translational research needed to validate these technologies will be conducted in patients with late-stage cancer and is expected to produce results of variable clinical significance and incidentally identify genetic risks. To explore the experiential context in which much of personalized cancer care will be developed and evaluated, we conducted a qualitative interview study alongside a pilot feasibility study of targeted DNA sequencing of metastatic tumor biopsies in adult patients with advanced solid malignancies. We recruited 29/73 patients and 14/17 physicians; transcripts from semi-structured interviews were analyzed for thematic patterns using an interpretive descriptive approach. Patient hopes of benefit from research participation were enhanced by the promise of novel and targeted treatment but challenged by non-findings or by limited access to relevant trials. Family obligations informed a willingness to receive genetic information, which was perceived as burdensome given disease stage or as inconsequential given faced challenges. Physicians were optimistic about long-term potential but conservative about immediate benefits and mindful of elevated patient expectations; consent and counseling processes were expected to mitigate challenges from incidental findings. These findings suggest the need for information and decision tools to support physicians in communicating realistic prospects of benefit, and for cautious approaches to the generation of incidental genetic information.European Journal of Human Genetics advance online publication, 17 July 2013; doi:10.1038/ejhg.2013.158.
European journal of human genetics: EJHG 07/2013; · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSEThe antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer. The addition of brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity. PATIENTS AND METHODS
Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m(2) intravenous loading dose followed by weekly maintenance of 250 mg/m(2) plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). The primary end point was overall survival (OS).ResultsA total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .12). Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). Partial responses observed (13.6% v 7.2%; P = .004) were higher in arm A. Incidence of any grade ≥ 3 adverse events was 78% in arm A and 53% in arm B. Fewer patients received ≥ 90% dose-intensity of both cetuximab (57% v 83%) and brivanib/placebo (48% v 87%) in arm A versus arm B, respectively. CONCLUSION
Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.
Journal of Clinical Oncology 05/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. Gemcitabine was administered at 1,000 mg/m(2) on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1). Results A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers). Conclusions RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0-24 h (AUC0-24) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified.
Investigational New Drugs 05/2013; · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Using sequencing information to guide clinical decision-making requires coordination of a diverse set of people and activities. In clinical genomics, the process typically includes sample acquisition, template preparation, genome data generation, analysis to identify and confirm variant alleles, interpretation of clinical significance, and reporting to clinicians. We describe a software application developed within a clinical genomics study, to support this entire process. The software application tracks patients, samples, genomic results, decisions and reports across the cohort, monitors progress and sends reminders, and works alongside an electronic data capture system for the trial's clinical and genomic data. It incorporates systems to read, store, analyze and consolidate sequencing results from multiple technologies, and provides a curated knowledge base of tumor mutation frequency (from the COSMIC database) annotated with clinical significance and drug sensitivity to generate reports for clinicians. By supporting the entire process, the application provides deep support for clinical decision making, enabling the generation of relevant guidance in reports for verification by an expert panel prior to forwarding to the treating physician.
[Show abstract][Hide abstract] ABSTRACT: The incorporation of molecular profiling into routine clinical practice has already been adopted in some tumor types, such as human epidermal growth factor receptor 2 (HER2) testing in breast cancer and KRAS genotyping in colorectal cancer, providing a guide to treatment selection that is not afforded by histopathologic diagnosis alone. It is inevitable that over time, with rapid advances in scientific knowledge, bioinformatics, and technology to identify oncogenic drivers, molecular profiling will complement histopathologic data to influence management decisions. Emerging technologies such as multiplexed somatic mutation genotyping and massive parallel genomic sequencing have become increasingly feasible at point-of-care locations to classify cancers into molecular subsets. Because these molecular subsets may differ substantially between each other in terms of sensitivity or resistance to systemic agents, there is consensus that clinical trials should be more stratified for or be performed only in such molecularly defined subsets. This approach, however, poses challenges for clinical trial designs because smaller numbers of patients would be eligible for such trials, while the number of novel anticancer drugs warranting further clinical exploration is rapidly increasing. This article provides an overview of the emerging methodologic challenges in the cancer genome era and offers some potential solutions for transforming clinical trial designs so they can identify new active anticancer regimens in molecularly defined subgroups as efficiently as possible.
Journal of Clinical Oncology 04/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:Targeted therapies elicit anticancer activity by exerting pharmacodynamic effects on specific molecular targets. Currently, there is limited use of pharmacodynamic assessment to guide drug administration in the routine oncology setting.Methods:We developed a phosphoshift (pShift) flow cytometry-based test that measures RAF signal transduction capacity in peripheral blood cells, and evaluated it in a phase II clinical trial of oral sorafenib plus low-dose cyclophosphamide in patients with advanced neuroendocrine tumours (NETs), in order to predict clinical course and/or guide individual dose-titration.Results:Twenty-two patients were enrolled. Median progression-free survival (PFS) was 3 months (95% CI 2-10.7), and one patient had a partial response. PFS was longer among five patients who demonstrated an increase in pShift after 7 days of sorafenib compared with those who did not (14.9 months vs 2.8 months; P=0.047). However, pShift did not add value to toxicity-based dose-titration.Conclusion:The pharmacodynamic assessment of RAF transduction may identify selected patients with advanced NETs most likely to benefit from the combination of sorafenib plus cyclophosphamide. Further investigation of this test as a potential biomarker is warranted.British Journal of Cancer advance online publication, 14 February 2013; doi:10.1038/bjc.2013.64 www.bjcancer.com.
British Journal of Cancer 02/2013; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSETo define human papillomavirus (HPV) -positive oropharyngeal cancers (OPC) suitable for treatment deintensification according to low risk of distant metastasis (DM). PATIENTS AND METHODSOPC treated with radiotherapy (RT) or chemoradiotherapy (CRT) from 2001 to 2009 were included. Outcomes were compared for HPV-positive versus HPV-negative patients. Univariate and multivariate analyses identified outcome predictors. Recursive partitioning analysis (RPA) stratified the DM risk.ResultsHPV status was ascertained in 505 (56%) of 899 consecutive OPCs. Median follow-up was 3.9 years. HPV-positive patients (n = 382), compared with HPV-negative patients (n = 123), had higher local (94% v 80%, respectively, at 3 years; P < .01) and regional control (95% v 82%, respectively; P < .01) but similar distant control (DC; 90% v 86%, respectively; P = .53). Multivariate analysis identified that HPV negativity (hazard ratio [HR], 2.9; 95% CI, 2.0 to 5.0), N2b-N3 (HR, 2.9; 95% CI, 1.8 to 4.9), T4 (HR, 1.8; 95% CI, 1.2 to 2.9), and RT alone (HR, 1.8; 95% CI, 1.1 to 2.5) predicted a lower recurrence-free survival (RFS; all P < .01). Smoking pack-years > 10 reduced overall survival (HR, 1.72; 95% CI, 1.1 to 2.7; P = .03) but did not impact RFS (HR, 1.1; 95% CI, 0.7 to 1.9; P = .65). RPA segregated HPV-positive patients into low (T1-3N0-2c; DC, 93%) and high DM risk (N3 or T4; DC, 76%) groups and HPV-negative patients into different low (T1-2N0-2c; DC, 93%) and high DM risk (T3-4N3; DC, 72%) groups. The DC rates for HPV-positive, low-risk N0-2a or less than 10 pack-year N2b patients were similar for RT alone and CRT, but the rate was lower in the N2c subset managed by RT alone (73% v 92% for CRT; P = .02). CONCLUSIONHPV-positive T1-3N0-2c patients have a low DM risk, but N2c patients from this group have a reduced DC when treated with RT alone and seem less suited for deintensification strategies that omit chemotherapy.
Journal of Clinical Oncology 01/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Attrition rates of drugs from human entry to regulatory approval are far higher in anticancer drugs than those for nononcology indications. In the era of molecular therapeutics that results from a deeper understanding in cancer biology and advancing technologies, the number of compounds available for clinical testing is likely to continue to increase. Although the main objectives of phase I trials are to characterize toxicities of new agents and to determine the recommended dose for phase II development, most phase I studies are now designed to provide some early signal on preliminary efficacy as secondary objectives. The "go-no-go" decision to further develop a drug, or not, is now often pushed forward to the phase I setting. Thus, there is a need for investigators to be able to critically review the preclinical data available in order to determine which drugs should advance on the developmental path. This review highlights the intrinsic characteristics of a drug and the relevant data to be collected during its preclinical assessment, which may maximize the chances of success in clinical testing and eventual regulatory approval.
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting. 01/2013; 2013:469-473.
[Show abstract][Hide abstract] ABSTRACT: s u m m a r y Objectives: To describe the natural course of distant metastases (DMs) following radiotherapy (RT) or chemoradiotherapy (CRT) in HPV(+) oropharyngeal carcinoma (OPC). Methods: OPC treated with RT/CRT from 1/1/2000 to 5/31/2010 were reviewed. The natural course of DM were compared between HPV(+) and HPV(À) cohorts. Results: Median follow-up was 3.9 years. The DM rate were similar (11% vs. 15% at 3-years, p = 0.25) between the HPV(+) (n = 457) vs. the HPV(À) (n = 167) cases. While almost all (24/25) HPV(À) DM occurred within 2-years following RT (1 was at 2.1 years), 7/54 (13%) of HPV(+) DM were detected beyond 3 years (up to 5.3 years). Disseminating to >2 organs occurred in 18 (33%) HPV(+) vs. none in HPV(À). Post-DM survival rates were 11% vs. 4% at 2-years (p = 0.02) for the HPV(+) vs. HPV(À) cases respectively. 5/6 HPV(+) with lung oligo-metastasis were still alive with stable disease beyond 2-years after salvage procedures for DM (chemotherapy: 3; surgical resection: 2; radiotherapy: 1). Conclusions: Although DM rates are similar, the natural course of HPV(+) DM differs from that of HPV(À) patients: it may occur after a longer interval, often with a ''disseminating'' phenotype, and a small num-ber may have prolonged survival after salvage for DM.
[Show abstract][Hide abstract] ABSTRACT: The phosphatidylinositol 3-kinase (PI3K) pathway is commonly deregulated in cancer. In recent years, the results of the first phase I clinical trials with PI3K inhibitors have become available. In comparison to other targeted agents such v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors in melanoma or crizotinib in anaplastic lymphoma receptor tyrosine kinase (ALK) translocated tumors, the number of objective responses to PI3K inhibitors is less dramatic. In this review we propose possible strategies to optimize the clinical development of PI3K inhibitors: by exploring the potential role of PI3K isoform-specific inhibitors in improving the therapeutic index, molecular characterization as a basis for patient selection, and the relevance of performing serial tumor biopsies to understand the associated mechanisms of drug resistance. The main focus of this review will be on PI3K isoform-specific inhibitors by describing the functions of different PI3K isoforms, the preclinical activity of selective PI3K isoform-specific inhibitors and the early clinical data of these compounds.
BMC Medicine 12/2012; 10(1):161. · 6.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
An open-label, multicenter, single-arm phase II trial was conducted to investigate the clinical activity of dacomitinib in recurrent/metastatic squamous-cell carcinoma of the head and neck (RM-SCCHN).Patients and methodsEligible patients were administered dacomitinib at 45 mg orally daily, in 21-day cycles. Primary end point was objective response rate.ResultsSixty-nine patients were enrolled with a median age of 62 years. Among response-evaluable patients, 8 [12.7%, 95% confidence interval (CI) 5.6% to 23.5%] achieved a partial response and 36 (57.1%) had stable disease, lasting ≥24 weeks in 9 patients (14.3%). The median progression-free survival (PFS) was 12.1 weeks and the median overall survival (OS) was 34.6 weeks. Most adverse events (AEs) were tolerable. The most common grade 3 or higher treatment-related AEs were diarrhea (15.9%), acneiform dermatitis (8.7%), and fatigue (8.7%). Treatment-related AEs led to at least one dose interruption in 28 (40.6%) patients and dose reductions in 26 (37.7%). Permanent treatment discontinuation occurred in 8 (11.6%) patients due to treatment-related AEs.Conclusions
Dacomitinib demonstrated clinical activity in RM-SCCHN, and the primary end point of this study was met. The toxicity profile of this agent was generally manageable with dose interruptions and adjustments.
[Show abstract][Hide abstract] ABSTRACT: The successes of targeted drugs with companion predictive biomarkers and the technological advances in gene sequencing have generated enthusiasm for evaluating personalized cancer medicine strategies using genomic profiling. We assessed the feasibility of incorporating real-time analysis of somatic mutations within exons of 19 genes into patient management. Blood, tumor biopsy and archived tumor samples were collected from 50 patients recruited from four cancer centers. Samples were analyzed using three technologies: targeted exon sequencing using Pacific Biosciences PacBio RS, multiplex somatic mutation genotyping using Sequenom MassARRAY and Sanger sequencing. An expert panel reviewed results prior to reporting to clinicians. A clinical laboratory verified actionable mutations. Fifty patients were recruited. Nineteen actionable mutations were identified in 16 (32%) patients. Across technologies, results were in agreement in 100% of biopsy specimens and 95% of archival specimens. Profiling results from paired archival/biopsy specimens were concordant in 30/34 (88%) patients. We demonstrated that the use of next generation sequencing for real-time genomic profiling in advanced cancer patients is feasible. Additionally, actionable mutations identified in this study were relatively stable between archival and biopsy samples, implying that cancer mutations that are good predictors of drug response may remain constant across clinical stages.
International Journal of Cancer 09/2012; · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the policy changes to decrease tobacco consumption and therapeutic advances in this disease, squamous cell carcinomas arising from the head and neck (HNSCC) continue to represent a common neoplasm and a leading cause of cancer-related mortality in Europe and worldwide. although different approaches have been evaluated, no treatment has currently been shown to be superior to cisplatin (Platinol, Corden Pharma) based chemoradiation in locally advanced HNSCC. Based on retrospective subgroup analyses from multiple large clinical trials, human papillomavirus (HPV) status has been shown to be a validated prognostic factor in oropharyngeal tumors. Patients with HPV-related tumors, especially those who are non-smokers, have generally excellent outcome as their tumors are highly sensitive to both chemotherapy and radiation, whereas those with tobacco-related and HPV-negative tumors, who continue to represent substantial number of cases in Europe, have worse prognosis with tumors that are more resistant to treatment. The goal of treatment de-intensification in patients with favorable risk is to avoid long-term and late toxicity, but this must be achieved without compromise of treatment efficacy. For those with risk factors that portend a worse prognosis, the question remains whether addition to or modification of conventional treatment regimens would improve upon therapeutic index. Innovative clinical trial designs specifically tailored to these risk groups are urgently needed.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: To describe the natural course of distant metastases (DMs) following radiotherapy (RT) or chemoradiotherapy (CRT) in HPV(+) oropharyngeal carcinoma (OPC). METHODS: OPC treated with RT/CRT from 1/1/2000 to 5/31/2010 were reviewed. The natural course of DM were compared between HPV(+) and HPV(-) cohorts. RESULTS: Median follow-up was 3.9years. The DM rate were similar (11% vs. 15% at 3-years, p=0.25) between the HPV(+) (n=457) vs. the HPV(-) (n=167) cases. While almost all (24/25) HPV(-) DM occurred within 2-years following RT (1 was at 2.1years), 7/54 (13%) of HPV(+) DM were detected beyond 3years (up to 5.3years). Disseminating to >2 organs occurred in 18 (33%) HPV(+) vs. none in HPV(-). Post-DM survival rates were 11% vs. 4% at 2-years (p=0.02) for the HPV(+) vs. HPV(-) cases respectively. 5/6 HPV(+) with lung oligo-metastasis were still alive with stable disease beyond 2-years after salvage procedures for DM (chemotherapy: 3; surgical resection: 2; radiotherapy: 1). CONCLUSIONS: Although DM rates are similar, the natural course of HPV(+) DM differs from that of HPV(-) patients: it may occur after a longer interval, often with a "disseminating" phenotype, and a small number may have prolonged survival after salvage for DM.
[Show abstract][Hide abstract] ABSTRACT: The Hedgehog (Hh) signaling pathway has been implicated in tumor initiation and metastasis across different malignancies. Major mechanisms by which the Hh pathway is aberrantly activated can be attributed to mutations of members of Hh pathway or excessive/inappropriate expression of Hh pathway ligands. The Hh signaling pathway also affects the regulation of cancer stem cells, leading to their capabilities in tumor formation, disease progression, and metastasis. Preliminary results of early phase clinical trials of Hh inhibitors administered as monotherapy demonstrated promising results in patients with basal cell carcinoma and medulloblastoma, but clinically meaningful anticancer efficacy across other tumor types seems to be lacking. Additionally, cases of resistance have been already observed. Mutations of SMO, activation of Hh pathway components downstream to SMO, and upregulation of alternative signaling pathways are possible mechanisms of resistance development. Determination of effective Hh inhibitor-based combination regimens and development of correlative biomarkers relevant to this pathway should remain as clear priorities for future research.
The Oncologist 07/2012; 17(8):1090-9. · 4.10 Impact Factor