April 2024
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9 Reads
Cancer Letters
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April 2024
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9 Reads
Cancer Letters
April 2024
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96 Reads
Journal of Thoracic Oncology
March 2024
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4 Reads
Cancer Research
Background and Purpose: Caveolin-1 (Cav-1), a scaffolding protein implicated in cellular signaling and membrane dynamics, undergoes intricate regulation at multiple levels. Recent evidence has suggested a potential association between oncogenic mutations and alterations in Cav-1 expression. Our study aimed to comprehensively explore how RAS/RAF mutations influence Cav-1 expression in cancer cells, as well as the underlying molecular mechanisms, using tetracycline (tet)-inducible cell lines and cancer cell lines harboring endogenous BRAF or KRAS mutations. Experimental Design: We assessed the regulation of Cav-1 expression using tet-inducible cell lines with BRAFV600E, KRASG12D, or KRASG12C mutations. We measured the half-life of Cav-1 at protein levels by using cycloheximide. We monitored Cav-1 localization and degradation dynamics by SNAP-based pulse-chase assay. Additionally, we performed protein and gene expression analyses by immunoblotting and qRT-PCR, luciferase reporter assay, and immunofluorescence to dissect the impact of BRAF and KRAS mutations on Cav-1 regulation at various stages of its life cycle. Results: We found a significant downregulation of Cav-1 at both mRNA and protein levels upon induction of BRAF or KRAS mutations. The use of KRASG12C, BRAFV600E, ERK, and/or MEK inhibitors in tet-inducible cell lines rescued the effects observed upon induction. The rescue effects have also been observed in H23, MiaPaCa-2 and 8505-C cancer cell lines bearing either BRAF or KRAS mutations. Notably, BRAFV600E exhibited a more pronounced reduction in Cav-1 expression than other mutations. We observed shortened half-life of Cav-1 at protein levels after induction of RAS/RAF mutations by using cycloheximide, and SNAP-based pulse-chase. These mutations accelerated lysosomal-mediated degradation of Cav-1 as determined by immunoblotting and immunofluorescence, which was reversed by lysosomal inhibitors. Conclusions: Our study establishes a novel regulatory paradigm wherein RAS/RAF mutations exert a multi-faceted influence on Cav-1 dynamics in cancer cells. The transcriptional and translational downregulation, coupled with accelerated lysosomal degradation, collectively contributes to the decreased half-life of Cav-1 following the induction of BRAF or KRAS mutations. These findings provide insights into the intricate molecular mechanisms underpinning the dysregulation of Cav-1 in the context of RAS/RAF mutations, offering potential avenues for therapeutic interventions. Citation Format: Veronica Castro Aceituno, Tiantian Cui, Haihua Feng, Linlin Yang, Sindhu Nair, Terence M. Williams. Regulation of caveolin-1 by RAS/RAF oncogenic signaling in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7080.
March 2024
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29 Reads
Science Advances
Pancreatic ductal adenocarcinoma (PDAC) is characterized by its nutrient-scavenging ability, crucial for tumor progression. Here, we investigated the roles of caveolae-mediated endocytosis (CME) in PDAC progression. Analysis of patient data across diverse datasets revealed a strong association of high caveolin-1 (Cav-1) expression with higher histologic grade, the most aggressive PDAC molecular subtypes, and worse clinical outcomes. Cav-1 loss markedly promoted longer overall and tumor-free survival in a genetically engineered mouse model. Cav-1–deficient tumor cell lines exhibited significantly reduced proliferation, particularly under low nutrient conditions. Supplementing cells with albumin rescued the growth of Cav-1–proficient PDAC cells, but not in Cav-1–deficient PDAC cells under low glutamine conditions. In addition, Cav-1 depletion led to significant metabolic defects, including decreased glycolytic and mitochondrial metabolism, and downstream protein translation signaling pathways. These findings highlight the crucial role of Cav-1 and CME in fueling pancreatic tumorigenesis, sustaining tumor growth, and promoting survival through nutrient scavenging.
March 2024
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4 Reads
Practical Radiation Oncology
March 2024
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72 Reads
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2 Citations
Journal of Thoracic Oncology
February 2024
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7 Reads
International Journal of Radiation Oncology*Biology*Physics
January 2024
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15 Reads
Clinical Colorectal Cancer
January 2024
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10 Reads
Journal of Clinical Oncology
341 Background: Definitive chemoradiation (CRT) is a standard-of-care for patients (Pts) with medically inoperable esophageal cancer (EC). The NRG/RTOG 0436 study of cisplatin/paclitaxel and RT (+/- cetuximab) as definitive therapy showed that about half of Pts have locally persistent disease. OBP-301 is a conditionally restricted, replication-competent adenovirus derived from human adenovirus type 5 that adds a human Telomerase Reverse Transcriptase (hTERT) gene promoter, replicating only in tumor cells to cause lysis. It may cause immunogenic cell death, enhance RT, and improve local control. OBP-301 was previously studied with RT in Japanese esophageal cancer Pts and shown to be safe and has promising activity. ¹ Methods: In NRG-GI007, a phase 1 study (NCT04391049), OBP-301 is added to weekly carboplatin/paclitaxel and RT (50.4 Gy/28 fractions) for Pts with medically inoperable EC. Pts receive 1-2mL of intratumoral OBP-301 1×10 ¹² virus particles/ml via endoscopy 3 days prior to and then at days 12 and 26 of CRT. The primary endpoint is dose-limiting toxicity (DLT), defined as adverse events (AEs, by CTCAE v5) definitely or probably attributed to OBP-301 that meet either of the following: (1) leading to a >14-day cumulative delay in CRT or (2) any grade ≥ 3 AE EXCEPT: grade 3 nausea/vomiting, grade 3 esophagitis or dehydration, first occurrence of grade 3/4 neutropenia, or grade 3/4 lymphopenia. Initially, 6 evaluable Pts (eligible and started protocol treatment) are enrolled. If protocol defined DLT occurs in ≤1 of 6 Pts, the dose will be deemed safe and an expansion cohort of 9 more will be enrolled to further assess safety and obtain a preliminary assessment of clinical complete response. If ≥2 Pts have a DLT then one de-escalated OBP-301 dose will be assessed. Results: From June 2020 to April 2023, 6 evaluable Pts were enrolled. Median age was 73.5 years, all male. Five Pts had adenocarcinoma and 1 had squamous cell carcinoma; 3 Pts had node-positive disease. All Pts received all planned OBP-301 injections, along with 50.4 Gy RT. Four out of 6 Pts received all 5 weekly doses of chemo for > 85% of planned total dose, and 2 got 4 weekly doses for > 70% of planned total dose. No Pt experienced ³7 day treatment delay. The following treatment-related (attributed as definitely, probably, or possibly related to CRT and/or OBP-301) grade 3 AEs were reported across 5 Pts: decreased neutrophil count (3 Pts), decreased lymphocyte count (2 Pts), decreased WBC (2 Pts), and fever and fatigue (1 Pt each). There were 4 Pts with AEs reported as definitely or probably related to OBP-301, all grade ≤2. No DLT occurred. Conclusions: No DLTs in the 6 evaluable Pts were observed and it is concluded that the initial OBP-301 dose level is safe. NRG-GI007 was reopened on August 7, 2023 to the expansion cohort. Full toxicity and treatment data will be presented. 1. Eur J Cancer 2021;153:98. Clinical trial information: NCT04391049 .
January 2024
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4 Reads
Cancer Research
Oncogenic mutations (such as in KRAS) can dysregulate transcription and replication leading to transcription conflicts (TRCs). Unresolved TRCs can cause lethal DNA damage. Here, we sought to investigate the causal role of oncogenic mutations in regulating TRCs in pancreatic ductal adenocarcinoma (PDAC). Further, we characterize the adaptive pathways that mitigate TRCs for PDAC survival. Human PDAC demonstrated 30-120-fold higher levels of TRC genomic signature compared to breast, colon and lung cancer (p<0.001). Gene expression analysis demonstrated high levels of known TRC resolution factors in human tumors compared to normal tissues. TRCs as measured by RNAPII-PCNA proximity ligation assay were significantly enriched in human PDAC cells (Panc-1, BxPC3, MiaPaca2) compared to immortalized normal HPNE cells (p<0.001). Similarly transcriptomic complexes were enriched in nascent DNA immunoprecipitates from Panc1 cells but not HPNE cells. Ectopic expression of oncogenic KRAS(G12D) in human pancreatic ductal epithelial (HPNE) cells enhanced TRCs, and TRC-related DNA:RNA hybrids (R-loops). Inhibition of KRAS or downstream effectors abrogated TRCs in Panc1 and MiaPaca2 cells. An siRNA screen identified several factors in the base-excision repair (BER) pathway as regulators of TRCs. Sub-lethal exposure to hydrogen peroxide enhanced TRCs, whereas N-acetyl cysteine abrogated TRCs. These findings were validated by a pharmacologic approach using inhibitors of APE1 endonuclease in BER pathway (Methoxyamine and CRT). Mechanistic studies revealed that BER pathway inhibition severely altered RNA polymerase II dynamics at nascent DNA; causing RNAPII trapping and contributing to enhanced TRCs. The ensuing DNA damage activated Chk2-ATR pathway but not Chk1-ATM pathway. Co-treatment with ATR inhibitor (VX970, 10-80nM) and BER inhibitor (methoxyamine, 6-12mM) at clinically relevant doses, synergistically enhanced DNA damage and reduced clonogenic survival in PDAC cells. The study uncovers a novel role of BER pathway defects and oxidative DNA damage in promoting TRCs. Our studies provide mechanistic insights into the regulation of TRCs in PDAC which has implications for genome instability and therapy in PDAC. Citation Format: Fan Meng, Anup K. Singh, Tiane Li, Marc Attiyeh, Fatemeh Kohram, Terence Williams, Yilun Liu, Mustafa Raoof. Base excision repair pathway regulates transcription-replication conflicts in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C065.
... The analyzed factors proved to be prognostic in earlier studies and are widely available throughout healthcare systems [17][18][19]. The pleural thickness in the CT scan was based on the International Association for the Study of Lung Cancer (IASLC) classification [9,20]. ...
March 2024
Journal of Thoracic Oncology
... A recent study conducted by Liu et al. compared the baseline drifts when using three reflector blocks versus using a single reflector block for calibrating of wall-mounted RGSC camera. 13 Their three-block method provides a new 9-point calibration scheme from a similar background to this study and results in a residual drift of 0.2 mm on an empty couch. Nevertheless, the most notable distinction between the two methods lies in our calibration incorporating a weight factor (70 kg). ...
November 2023
... Other research has shown that ciprofloxacin can slow the growth of hepatocellular carcinoma cell lines; its mechanisms of action include DNA breaks, and the inhibition of topoisomerases. Furthermore, ciprofloxacin has a synergistic effect when combined with cisplatin in this regard [23]. ...
Reference:
APJCP Volume 25 Issue 4 Pages 1433-1440
November 2023
Practical Radiation Oncology
... Nonetheless, resistance to radiotherapy often develops, leading to tumor recurrence and metastasis, thereby compromising treatment outcomes [3,4]. Consequently, there is an urgent need for accurate biomarkers to predict and enhance the sensitivity of esophageal cancer to radiotherapy. ...
August 2023
International Journal of Radiation Oncology*Biology*Physics
... Stereotactic body radiation therapy (SBRT) is a safe and effective treatment option for patients with earlystage non-small cell lung cancer (NSCLC). While 5-year local tumor control rates after SBRT are greater than 90% [1, 2], isolated primary tumor site progression can occur in the absence of metastatic disease due to biological radio-resistance [3], insufficient doses delivered to tumor target [4], or potential marginal misses during treatment delivery due to inaccurate image guidance delivery systems [5]. Secondary treatment options for isolated primary tumor site progression after SBRT include salvage lung resection, re-irradiation with external beam radiation therapy (EBRT), or percutaneous ablative procedures (cryotherapy, microwave ablation, radio-frequency ablation) [6,7]. ...
August 2023
Cancer
... Linlin Yang et al. engineered EGFR apt -3WJ-siKRAS G12C nanoparticles targeting KRAS mutations, effectively reducing KRAS G12C expression in H2122, H2030, and H1299 cells. This innovation inhibited the downstream MAPK pathway and amplified the tumor-suppressive impact of radiotherapy(73). ...
July 2023
Molecular Therapy — Nucleic Acids
... The recurrence risk of TNBC is higher in the first few years following diagnosis, and it tends to be more aggressive [5]. While surgery, chemotherapy, and/or radiotherapy are the mainstays of treatment, intrinsic or acquired resistance results in poor clinical outcomes [6][7][8]. ...
July 2023
Cancer Letters
... By providing interpretable and accurate toxicity predictions, our models could enhance the decision-making process in radiation therapy. The use of Shapley values adds a layer of interpretability that is vital for clinical acceptance and application [30]. Clinicians can leverage these insights to understand the key factors influencing toxicity risk, allowing for more informed and personalized patient care strategies [31]. ...
July 2023
International Journal of Radiation Oncology*Biology*Physics
... The advent of MR-guided radiotherapy (MRgRT), have greatly improved the precision of abdominal radiotherapy (RT) [1]. One system currently available for MRgRT, the Unity 1.5 T MR-linac (Elekta, Stockholm, Sweden), can acquire daily MR images of patients at each fraction of RT, allowing radiation oncologists to verify and adaptively adjust the reference plan based on changes in anatomic structures during treatment, ensuring target dose coverage while protecting organs at risk [2][3][4][5][6][7]. ...
May 2023
... Over the past 100 years, the knowledge and understanding regarding the biological response of various cells and tissues to ionizing radiation have been accumulating continuously. The advances in radiation biology have greatly improved outcomes and survival rates and reduced side effects of radiotherapy in cancer patients [13][14][15][16]. However, the mechanisms for the sensitive otherness and variation of cancer responses to radiation have not been fully explored. ...
March 2023
Surgical Oncology Clinics of North America