tbuckley/cabot-search huggingface dataset:
Abstract 1215: DIRAS3 inhibits oncogenic RAS signaling and RAS-dependent cell growth driven by prevalent KRAS hot spot mutations
Authors: Gamze Bildik, Junchen Liu, Weiqun Mao, Hailing Yang, John F. Hancock, Robert C. Bast, Zhen Lu
Journal: Cancer Research (2024)

Abstract RAS mutations are found in 30% of human cancers and are characterized by hotspot mutations at codons G12, G13, and Q61. This results in constitutively activated RAS proteins. Despite recent advances in drug design and the emergence of covalent inhibitors, effectively targeting mutant RAS remains challenging. Our group previously identified the tumor suppressor protein DIRAS3, which directly binds Ras and inhibits its function by disrupting KRAS dimers/nanoclusters and blocking effector activation. DIRAS3 expression reduced cancer cell growth in pancreatic and ovarian cancers. To determine whether DIRAS3 plays a definitive role in inhibiting mutant KRAS, we comprehensively characterized DIRAS3's RAS-inhibitory effects using RASless mouse embryo fibroblast (MEF) cells as a model system lacking endogenous RAS isoforms. We ectopically expressed various KRAS mutations in these cells and then examined DIRAS3's effect on each KRAS mutant clone. We analyzed downstream RAS signaling, colony formation, cell viability, and toxicity. Our results showed that DIRAS3 significantly inhibited RAS-dependent colony formation in KRAS mutant (G12C, G12D, G12V, G13D, G12R, Q61R, Q61L) but not wild-type KRAS clones. However, when we added epidermal growth factor (EGF) to the medium, DIRAS3 expression inhibited wild-type KRAS activity, decreasing colony formation. This suggests that DIRAS3 selectively affects the active, GTP-bound form of KRAS and downstream signaling. Additionally, DIRAS3 expression decreased Erk1/2 phosphorylation in MEF cells with mutant KRAS, but not in the cells with a BRAFV600E mutation. This indicates that DIRAS3 specifically inhibits the KRAS-mediated MEK/ERK signaling, cell proliferation, and cytotoxicity. Moreover, to determine the critical region for DIRAS3's RAS-inhibitory function, we compared wild-type DIRAS3 and deletions (ΔNTE, ΔCTE, ΔNCTE). Our results showed both termini are required to effectively suppress clonogenic growth, emphasizing the requirement for DIRAS3 to anchor to the plasma membrane and interact with the RAS dimer interface to inhibit RAS-dependent tumor growth. In conclusion, our findings underscore the potent and specific inhibitory effects of DIRAS3 on RAS-driven oncogenesis, positioning it as a promising pan-RAS inhibitor for RAS-mutant cancers. Citation Format: Gamze Bildik, Junchen Liu, Weiqun Mao, Hailing Yang, John F. Hancock, Robert C. Bast, Zhen Lu. DIRAS3 inhibits oncogenic RAS signaling and RAS-dependent cell growth driven by prevalent KRAS hot spot mutations [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 1215.
Abstract 5879: Role of the inner mitochondrial membrane protein (Mic60) in MAPKi-resistant melanoma
Authors: Jagadish C. Ghosh, Segundo Del Aguila, Haiyin Li, Jessie Villanueva, Dario C. Altieri
Journal: Cancer Research (2024)

Abstract Introduction: Metastatic melanoma is one of the most aggressive cancers, despite recent improvements in therapy. The rising melanoma incidence and mortality, along with its high propensity for metastasis highlights the urgency to find more effective therapeutic targets. The efficacy of targeted MAPK signaling pathway inhibitors (MAPKi) in metastatic melanoma therapy is limited by the development of resistance mechanisms that result in disease relapse. This situation necessitates alternative treatments for melanoma patients who develop resistance to targeted therapy. We have recently found out that there exists a group of human tumors that express lower levels of Mic60, a mitochondrial structural protein also known as mitofilin or inner membrane mitochondrial protein (IMMT). In a model of prostate cancer, we showed that Mic60-low tumors have lower mitochondrial fitness, but increased cell motility, invasion, and propensity to metastasize. However, a potential differential expression of Mic60 in melanoma has not been investigated and whether reduced mitochondrial fitness in Mic60-low tumors can expose new therapeutic vulnerabilities in combination with targeted therapies has not been determined. Experimental Procedures: We analyzed melanoma-specific TMA for differential expression of Mic60 in tumor vs. adjacent normal tissue by IHC. Differential mRNA expression levels were examined by single-cell RNA-Seq and quantified by bioinformatics analysis. Differential therapeutic vulnerabilities of Mic60-low melanoma cell lines to mitochondrial-targeted small molecule Hsp90 inhibitor, Gamitrinib, were assessed for cell death induction and mitochondrial dysfunction. Results: We identified subsets of melanoma patients with constitutively reduced or outright undetectable expression of Mic60, in vivo. By single-cell RNA-Seq, Mic60-low melanomas were characterized by reduced oxidative phosphorylation and decreased ATP production, slower cell cycle progression but paradoxically increased cell motility and invasion. Loss of Mic60 exposed new, actionable therapeutic vulnerabilities, and the combination of Gamitrinib plus MAPKi potently induced mitochondrial cell death in MAPKi-resistant melanoma cell lines. Conclusion: Mic60 is heterogeneously expressed and often reduced in melanoma. Although this is associated with increased cell invasion and metastatic propensity, the combination of Gamitrinib plus MAPKi restored mitochondrial cell death in therapy-resistant, Mic60-low melanoma cells. Citation Format: Jagadish C. Ghosh, Segundo Del Aguila, Haiyin Li, Jessie Villanueva, Dario C. Altieri. Role of the inner mitochondrial membrane protein (Mic60) in MAPKi-resistant melanoma [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 5879.
Abstract 1660: Tumor pharmacokinetics and pharmacodynamics assessment of TEAD inhibitor VT03989 in patient-derived xenograft models of glioblastoma
Authors: Tigran Margaryan, Yu-Wei Chang, Jennifer Molloy, Barbara Hopkins, Mackenna Elliott, Ernesto Luna Melendez, Connor White, Nader Sanai, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta
Journal: Cancer Research (2024)

Abstract Background: The Hippo-YAP/TAZ pathway regulates cell proliferation, cell growth and migration. The major effectors of the Hippo pathway are the TEAD transcription factors, which are deregulated in several cancers, including glioblastoma (GBM). In this study, we evaluated the pharmacokinetics and pharmacodynamics of VT03989, a highly potent TEAD inhibitor, in orthotopic patient-derived xenograft (PDX) models of GBM. Methods: Mice with intracranial PDX GBM tumors were randomized into two cohorts to receive 10 mg/kg (oral) VT03989 or placebo for 4 days. VT03989 levels in plasma, tumor, and contralateral brain tissue were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) at 2, 6, and 12 hours after the last treatment of VT03989. Unbound fractions were determined by equilibrium dialysis. Quantitative RT-PCR was performed to assess levels of TEAD target genes, CTGF and CYR61. Immunohistochemistry of Ki67 and cleaved caspase 3 (CC3) was performed. Results: The median unbound concentrations of VT3989 were 27 nM in plasma and 26 nmol/kg in the tumor. The median brain-to-plasma and tumor-to-plasma partition coefficients of unbound VT03989 were 0.65 and 0.99, respectively - indicating favorable brain and tumor penetration ability of VT03989. A decrease in CTGF and CYR61 indicated TEAD inhibition and was accompanied by an increase in CC3 (+) cells. Conclusion: VT03989 is well tolerated, achieves pharmacologically relevant unbound concentrations in GBM PDX models, and is associated with significant target modulation. Ongoing studies are evaluating in vivo survival benefits from combining VT03989 inhibition with radiation therapy Citation Format: Tigran Margaryan, Yu-Wei Chang, Jennifer Molloy, Barbara Hopkins, Mackenna Elliott, Ernesto Luna Melendez, Connor White, Nader Sanai, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta. Tumor pharmacokinetics and pharmacodynamics assessment of TEAD inhibitor VT03989 in patient-derived xenograft models of glioblastoma [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 1660.
Abstract 1659: Phosphorylation of cell cycle and apoptosis regulatory protein (CARP)-1 by stress-activated protein kinase P38γ is a novel mechanism of apoptosis signaling by genotoxic chemotherapy
Authors: Jaganathan Venkatesh, Magesh Muthu, Vino T. Cheriyan, Sreeja C. Sekhar, Nuwan C. Acharige, Edi Levi, Hadeel Assad, Mary Kay Pflum, Arun K. Rishi
Journal: Cancer Research (2024)

Abstract CARP-1, a perinuclear phospho-protein, regulates cell survival and apoptosis signaling induced by genotoxic drugs. However, kinase(s) phosphorylating CARP-1 and down-stream signal transduction events remain unclear. Here we find that CARP-1 Serine (S)626 and Threonine (T)627 substitution to Alanines (AA) inhibits genotoxic drug-induced apoptosis. CARP-1 T627 is followed by a Proline (P), and this TP motif is conserved in vertebrates. To further elucidate chemotherapy-activated, CARP-1-dependent signaling mechanisms, we UV cross-linked protein extracts from Adriamycin-treated HeLa cervical cancer cells with a CARP-1 (614-638) peptide, and conducted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses of the peptide-bound protein complexes. This experiment revealed SAPK p38γ interaction with CARP-1 (614-638) peptide. Our studies further revealed that SAPK p38γ phosphorylates CARP-1 T627 in cancer cells treated with genotoxic drugs. CARP-1 T627 phosphorylation was also noted in breast tumors from patients treated with radiation or endocrine therapies. Loss of p38γ abrogates CARP-1 T627 phosphorylation, and results in enhanced survival of breast cancer cells by genotoxic drugs. We conclude that genotoxic drugs activate p38γ-dependent CARP-1 T627 phosphorylation and cell growth inhibition. Citation Format: Jaganathan Venkatesh, Magesh Muthu, Vino T. Cheriyan, Sreeja C. Sekhar, Nuwan C. Acharige, Edi Levi, Hadeel Assad, Mary Kay Pflum, Arun K. Rishi. Phosphorylation of cell cycle and apoptosis regulatory protein (CARP)-1 by stress-activated protein kinase P38γ is a novel mechanism of apoptosis signaling by genotoxic chemotherapy [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 1659.
Abstract 1297: Patient engagement: Improving the at home care for cancer patients in treatment
Authors: Robert Blomquist
Journal: Cancer Research (2024)

Abstract CareBOX Program is an Austin-based non-profit founded in 2014 to address a serious gap in cancer care for patients in the Central Texas area. It provides essential nutritional supplements and supplies to help prevent malnutrition, infections, and injuries from falls as patients continue at-home recovery during treatment and following surgery. About 80 percent of the supplies CareBOX Program provides are not covered by insurance. Many patients could not afford to purchase these items on their own. Volunteers deliver the CareBOXes to the clients’ homes. CareBOX Program has always been an inclusive organization. We operate on the basis that all cancer patients in Central Texas in need of our services will receive them as long as we have the funding to do so. Our youngest patient has been 3 months old and our oldest patient has been 93 years old. Currently we are serving more women (61%) than men (39%). Approximately 67% of patient households report annual income of less than $35,000. To date, CareBOX program volunteers have delivered more than 3,800 CareBOXes Citation Format: Robert Blomquist. Patient engagement: Improving the at home care for cancer patients in treatment [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 1297.
Abstract 4655: Targeting FAK improves the tumor penetration of antibody-drug conjugates to strengthen the anti-cancer responses
Authors: Baoyuan Zhang, Zhixiang Zhang, Jiaming Gao, Shiqiang Lu, Ran Pang, Dongfang Li, Xun Huang, Natasha Qin, Leo Liu, Zaiqi Wang
Journal: Cancer Research (2024)

Abstract Antibody-drug conjugates (ADCs) such as HER2 ADC Enhertu and TROP2 ADC Trodelvy have been proved to be the promising therapeutic agents in portion of cancer diseases. However, there are still numerous patients refractory to the therapy, indicating that the efficacy of ADCs may need to be further optimized. Here, we report that the excessive cancer-associated fibroblasts (CAFs) can serve as a fibrotic barrier, to the detriment of anti-tumor effects from ADCs by alleviating their tissue penetration. Mechanistically, the cancer cells can transform the normal fibrotic cells into CAFs which are featured by the hyperactivated focal adhesion kinase (FAK) signaling. The fast-growing CAFs would decrease the tumor uptake of the big molecules, conferring drug resistance of ADCs to the cancer cells. Targeting FAK with a small molecule inhibitor IN10018 is capable to reduce CAFs associated tumor barrier, elevating the tissue penetration of different types of ADCs regardless their respective targets. The combination regimen comprising IN10018 and the ADCs targeting either HER2 or TROP2 outperformed each monotherapy with respect to antitumor outcomes in different animal experiments. The preclinical evidence for the dual regimen of IN10018 and ADCs warrants a further validation in clinical settings. Citation Format: Baoyuan Zhang, Zhixiang Zhang, Jiaming Gao, Shiqiang Lu, Ran Pang, Dongfang Li, Xun Huang, Natasha Qin, Leo Liu, Zaiqi Wang. Targeting FAK improves the tumor penetration of antibody-drug conjugates to strengthen the anti-cancer responses [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 4655.
Abstract 138: UCHL5 and PAX3-FOXO1 resolve replication stress in rhabdomyosarcoma
Authors: Amit J. Sabnis, Pushpendra K. Sahu, Yue Pan
Journal: Cancer Research (2024)

Abstract PAX3-FOXO1 positive rhabdomyosarcoma (RMS) is an aggressive pediatric sarcoma with a terrible prognosis. The resultant fusion acts as a chimeric transcription factor, in part remodeling chromatin to inhibit terminal differentiation and maintain cancer cell proliferation. As this oncoprotein is not directly druggable, we have used genetic screens to identify dependencies downstream of PAX3-FOXO1 to improve our understanding of pathogenesis and develop new therapeutic targets. We performed pooled CRISPRi screening in an isogenic system of a patient-derived RMS cell line with or without knockdown of PAX3-FOXO1. Loss of the ubiquitin hydroxylase UCHL5 led to selective depletion of PAX3-FOXO1 positive Rh30 cells compared to PAX3-FOXO1 knockdown cells, suggesting that the fusion creates UCHL5 dependence. We validated this finding in competition growth assays in additional fusion positive (FP) and fusion negative (FN) RMS cell lines, and observed UCHL5 dependency only in the former. By contrast, UCHL5 was dispensable for cell growth and survival in FN RMS cell lines. These data were recapitulated in the large DepMap dataset, which also identified the top genetic co-dependencies of UCHL5 as INO80-complex (INO80c) members. We therefore investigated whether the fusion selective effects of UCHL5 were mediated by the INO80c, of which UCHL5 is an N-terminal member. We observed that knockdown of another N-terminal component of INO80c, NFRKB, phenocopies the fusion-selective effects of UCHL5 loss. Conversely, the catalytic ATPase INO80 was pan-essential, suggesting that only N-terminal subunits of INO80c regulate PAX3-FOXO1 specific functions. INO80c plays an essential role in mitigating DNA replication stress. Indeed, loss of UCHL5 led to DNA damage as measured by γH2AX and slowing of replication forks as measured by fiber assays in FP, but not FN RMS. Unexpectedly, acute degradation of PAX3-FOXO1 also slowed DNA replication fork speed, suggesting a genetic model in which UCHL5 and PAX3-FOXO1 cooperate to resolve replication stress in FP RMS. Finally, in vivo experiments using cell line xenografts confirms that loss of UCHL5 slows the growth of FP RMS, but not FN RMS. These findings suggest that loss of UCHL5 induces replication stress in a fusion-specific manner, and offers both an opportunity to study the mechanisms by which the PAX3-FOXO1 oncoprotein mitigates replication stress, and to develop UCHL5 inhibitors as precision therapies for FP RMS patients. Citation Format: Amit J. Sabnis, Pushpendra K. Sahu, Yue Pan. UCHL5 and PAX3-FOXO1 resolve replication stress in rhabdomyosarcoma [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 138.
Abstract 5515: Low body mass index (BMI) induces neuronal NPY and promotes brain metastasis of lung cancer
Authors: Abhishek Tyagi, Shih-Ying Wu, Ravindra Deshpande, Kerui Wu, Liang Liu, Kounosuke Watabe
Journal: Cancer Research (2024)

Abstract Brain metastases (BrMs) are a common occurrence in lung cancer with a dismal outcome. To develop a more effective therapeutic strategy, it is crucial to understand the underlying pathological mechanism of brain metastasis. Recent clinical data has unveiled a significant association between low body mass index (BMI) and an increased risk of brain metastasis in lung cancer patients, leading to reduced survival rates compared to other primary tumors. However, the molecular mechanism underlying this paradoxical relationship, often referred to as the "obesity paradox," in the context of lung cancer mortality presents a complex and intriguing puzzle and warrants in-depth investigation. Here, we examined biological mechanism of how low BMI promotes lung cancer brain metastasis. In this study, we conducted a retrospective pan-analysis of 5,516 patient cohorts with brain metastasis originating from lung, breast, melanoma, and renal cancers with their BMI status. We found that lung cancer patients with low BMI have significantly higher brain metastatic incidence compared to the high BMI patients, in contrast to breast, melanoma, and renal cancers. Furthermore, we found that low BMI plays a pivotal role in mediating neuron activation within the brain and that the secretion of neuronal neuropeptide Y (NPY), a protein involved in appetite and energy homeostasis via GHSR-receptor manner, promotes metabolic switching through NPY/NPY5R axis in the tumor cells in the brain thereby enabling metastasis. Elevated levels of neuronal NPY in the brains of cancer-free subjects with low BMI suggest its potential utility as a promising prognostic biomarker for identifying the increased risk of metastatic disease in lung cancer patients with low BMI. We also demonstrated that reversing low BMI or blocking the NPY/Y5R interactions effectively abrogated brain metastasis in our animal model. Our findings suggest a novel pro-metastatic role of low BMI-induced NPY in the progression of brain metastasis. We emphasize the importance of elucidating the clinical implications of this relationship to develop an updated intervention strategy for the clinical care of patients with lung cancer and low BMI. Citation Format: Abhishek Tyagi, Shih-Ying Wu, Ravindra Deshpande, Kerui Wu, Liang Liu, Kounosuke Watabe. Low body mass index (BMI) induces neuronal NPY and promotes brain metastasis of lung cancer [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 5515.
Abstract 7487: Construction of a reliable CTC detection method and validity evaluation of CTC markers in colorectal cancer
Authors: Yusuke Takahashi, Yuichi Ijiri, Shiki Fujino, Nakhaei Elnaz, Ayuko Kishimoto, Kentaro Shirai, Shigeki Iwanaga, Masatoshi Yanagida, Ali Asgar Bhagat, Norikatsu Miyoshi
Journal: Cancer Research (2024)

Abstract Even in modern times when medical technology has advanced, cancer remains a life-threatening disease, and recurrence and metastasis are major issues in cancer treatment. The characteristics of cancer cells change with progression and treatment. Therefore, timely evaluation on their characteristics and decision on the treatment strategy are required. Circulating tumor cells (CTCs) are released into blood vessels in solid tumors and promote metastasis by circulating in the blood. CTCs are thus attractive targets for liquid biopsy and can provide useful information for selection of appropriate treatment. To obtain reliable results from CTC testing, it is important to prove that the detected cells are derived from cancerous tissue. In molecular tests targeting CTCs, it is still unclear whether the detected cells are derived from cancer tissue displaying genetic mutations. Aiming to establish reliable CTC testing, we have developed a simple method using molecular imaging flow cytometry to detect APC gene mutation together with Cytokeratin and Vimentin, which are epithelial-mesenchymal transition markers. Since, abnormalities in the APC gene are detected in 60-70% of colorectal cancer patients, detecting such mutations provides strong evidence that the detected cells are derived from cancerous tissue. Here, we show that upon evaluation of analytical performance of our method using cells isolated from cancerous tissue, our method showed high concordance rate against APC gene mutation. A clinical proof-of-concept using 5 mL of whole blood from colorectal cancer patients revealed that counts of cells with APC mutation in blood and cells with Cytokeratin and/or Vimentin expression in blood are highly correlated. Our results demonstrated a pathological stage-dependent increase in the count and frequency of Cytokeratin and/or Vimentin positive CTCs. We believe that our study not only establishes a practical approach for identifying CTCs in cancer patients but also provides potential implications in clinical practice, prognostic evaluation, and selection of treatment strategies. Citation Format: Yusuke Takahashi, Yuichi Ijiri, Shiki Fujino, Nakhaei Elnaz, Ayuko Kishimoto, Kentaro Shirai, Shigeki Iwanaga, Masatoshi Yanagida, Ali Asgar Bhagat, Norikatsu Miyoshi. Construction of a reliable CTC detection method and validity evaluation of CTC markers in colorectal cancer [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 7487.