tbuckley/cabot-search huggingface dataset:
Abstract 678: Experimental therapy of triple negative breast cancer with next-generation of MDM2 inhibitors
Authors: Wei Wang, Hao Chen, Yang Xie, Sayantap Datta, Wei Li, Ruiwen Zhang
Journal: Cancer Research (2024)

Abstract Patients with triple-negative breast cancer (TNBC) typically experience minimal benefits from the existing hormonal or trastuzumab-based therapies, necessitating reliance on chemotherapy as the predominant treatment approach, which, unfortunately, is limited by insufficient efficacy, significant side effects, and the development of drug resistance. These issues highlight an urgent demand for the discovery and development of more effective and safer therapeutics for TNBC. Overexpression and amplification of the MDM2 oncogene frequently occur in TNBC, which is associated with invasive and high-grade/late-stage tumors, metastasis, and recurrence, and is an independent negative prognostic factor for TNBC patients. Extensive studies have indicated that MDM2 represents a novel molecular target for TNBC. Thus far, multiple strategies aiming at MDM2 inhibition have not succeeded in Phase II-III clinical trials, largely due to factors like inadequate efficacy, significant drug toxicity, and emergence of resistance. In addition, TNBC tumors commonly harbor mutant p53, and the existing MDM2 inhibitors that block p53-MDM2 binding and depend on wild-type p53 expression in the tumor to exert anticancer effects would have little or no clinical responses or even induce resistant clones by increasing MDM2 expression and its oncogenic activity. Therefore, there is a need for developing new-generation MDM2 inhibitors that are p53-independent. We recently discovered a novel class of MDM2 degraders, representing a paradigm shift in the strategy of targeting MDM2. One of these analogs, WW68, was identified as a potent and selective MDM2 inhibitor. Its in vitro and in vivo anti-breast cancer activities and underlying mechanisms of action were evaluated in breast cancer cell lines with various p53 backgrounds. Our results demonstrate that WW68 effectively induces MDM2 protein degradation. It selectively inhibits breast cancer cell growth, decreases cell proliferation, and induces G2/M phase arrest and apoptosis in breast cancer cells, regardless of p53 status. Notably, in clinically relevant TNBC PDX models, WW68 inhibited MDM2 and suppressed tumor growth without causing host toxicity. In conclusion, WW68 represents a new class of MDM2 inhibitor that exerts its anticancer activity through directly down-regulating MDM2, and may be developed as a novel anti-TNBC therapeutic agent. (Supported by NIH R01CA214019 and R01CA240447; and DoD W81XWH2010011) Citation Format: Wei Wang, Hao Chen, Yang Xie, Sayantap Datta, Wei Li, Ruiwen Zhang. Experimental therapy of triple negative breast cancer with next-generation of MDM2 inhibitors [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 678.
Abstract 4506: Discovery of potent, highly selective and orally efficacious SMARCA2 degraders
Authors: Lingying Leng, Lin Yang, Wenbin Tu, Rohan Rej, Srinivasa Rao Allu, Liyue Huang, Wei Jiang, Yu Wang, Jeanne Stuckey, Farzad R Sarkari, Meilin Wang, Lu Wang, Bo Wen, Duxin Sun, Shaomeng Wang
Journal: Cancer Research (2024)

Abstract In human non-small cell lung cancer, melanoma and other types of human cancers, the mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated, which leads to inactivation of its functions. SMARCA2, a close homologous protein of SMARCA4, is an attractive synthetic lethality target for human cancers with SMARCA4 deficiency. Herein, we report the discovery and biological evaluation of potent, highly selective, orally efficacious SMARCA2 PROTAC degraders exemplified by UM-SMD-8801. UM-SMD-8801 has DC50 &amp;lt;10 nM and Dmax &amp;gt;90% against SMARCA2 and &amp;gt;1,000-fold degradation selectivity over SMARCA4. Consistently, UM-SMD-8801 potently inhibits cell growth in SMARCA4 mutated cancer cell lines with low nanomolar IC50 values and shows &amp;gt;100-fold weaker activity in SMARCA4 wild-type cancer cell lines. UM-SMD-8801 has a good overall pharmacokinetic profile and an excellent oral bioavailability in mice. Oral administration of UM-SMD-8801 is highly effective in reducing SMARCA2 protein by &amp;gt;90% in tumor tissues in mice, while having minimal effect on SMARCA4 protein. UM-SMD-8801 represents a very promising SMARCA2 degrader for extensive evaluation as a potential new therapy for the treatment of SMARCA4-deficient human cancers. Citation Format: Lingying Leng, Lin Yang, Wenbin Tu, Rohan Rej, Srinivasa Rao Allu, Liyue Huang, Wei Jiang, Yu Wang, Jeanne Stuckey, Farzad R Sarkari, Meilin Wang, Lu Wang, Bo Wen, Duxin Sun, Shaomeng Wang. Discovery of potent, highly selective and orally efficacious SMARCA2 degraders [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 4506.
Abstract 5934: Ferroptosis induction therapy for castration resistant prostate cancer
Authors: Mojisoluwa Awolowo, Precious Elechi Dike, Valerie Odero-Marah
Journal: Cancer Research (2024)

Abstract Prostate cancer (PCa) is the most common non-skin cancer in men, and second leading cause of death. The fundamental treatment for treating PCa is androgen deprivation therapy which is an effective form of treatment initially. Nevertheless, the disease reoccurs in most men; this is referred to as castration-resistant PCa (CRPC), for which the standard treatment is enzalutamide. However, some develop resistance to this enzalutamide anti-androgen agent. Ferroptosis is an iron-dependent lipid peroxidation form of regulated cell death being investigated as a novel potential therapy for PCa using ferroptosis inducers such as RSL3; they have shown promise in selectively triggering cell death in cancer cells while sparing healthy tissues. We hypothesize that RSL3- induced ferroptosis will overcome enzalutamide resistance in PCa cells. To test this, we utilized C4-2B MDVR cells which represents a cell model for aggressive PCa that metastasized to the bone and is resistant to both castration therapy and the enzalutamide drug treatment. C42B-MDVR cells were treated with increasing concentrations of RSL3 followed by analysis of cell viability with MTS assay. A dose dependent reduction in cell viability was observed which was reversed by ferroptosis inhibitor, ferrostatin-1. Western blot analysis revealed a decreased expression of the antioxidant enzyme glutathione peroxidase 4 (GPX4) with ferroptosis induction indicating a mechanism of the RSL3-induced cell death. The limitations to our research are that the research was performed in vitro and have not been tested on mouse models to visualize the effects of the treatments in animals. In conclusion, ferroptosis inducer RSL3 decreases GPX4 expression and decreases proliferation of PCa cells while ferrostatin-1 reverses the effects of the RSL3 treatment. Thus, ferroptosis inducers present a potential novel therapeutic approach for CRPC patients who have developed resistance to conventional androgen therapies. NIH NIGMS RISE 5R25GM058904, NIH/NIMHD U54MD007590; U54MD013376 Citation Format: Mojisoluwa Awolowo, Precious Elechi Dike, Valerie Odero-Marah. Ferroptosis induction therapy for castration resistant prostate 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 5934.
Abstract 6357: Establishing a reverse translational platform to dissect mode of action and mechanisms of resistance to GUCY2C-CD3 T cell engager
Authors: Joana Borlido, Jade Lolarga, Rachael Whaley, Michael A. Damore, Cen Guo, Keith Abayasiriwardana, Xiaojun Xu, Maggie Liu, Gosia Nocula-Lugowska, Sam Stoner, Christopher Kraser, Ioanna Cheronis, Maria Delioukina, Lee Clark, Raj Bhadra, Murali Gururajan
Journal: Cancer Research (2024)

Abstract PF-07062119 (GUCY2C x CD3), a bispecific T cell engager (TCE) targeting Guanylyl Cyclase C (GUCY2C), a GI tumor associated antigen, is currently being evaluated in a Phase 1 clinical trial in colorectal cancer (CRC) and other GI malignancies. Improved pre-clinical understanding of the correlates of PF-07062119 resistance mechanisms and PD in a human disease relevant context is critical to better inform drug combination and patient selection strategy. Due to limited translatability of mouse syngeneic tumor models, establishing a more human disease-relevant platform leveraging tumor patient material to better inform PF-07062119 clinical strategy is needed. Here, we will discuss our efforts to perform immune profiling of T cell and myeloid tumor infiltrates, and to evaluate tumor cell depletion and cytokine production of colorectal carcinoma (CRC) samples treated ex vivo with PF-07062119. This platform may be leveraged to 1) provide clinically relevant disease insights to the effect of TCEs across a range of tumor indications; 2) determine impact of different combinatorial partners on tumor cell killing to inform clinical decisions; 3) address questions related to the minimal efficacy of TCEs in the solid tumor space; and 4) provide potential solutions for future combination partners to overcome immunosuppression in the tumor microenvironment. Citation Format: Joana Borlido, Jade Lolarga, Rachael Whaley, Michael A. Damore, Cen Guo, Keith Abayasiriwardana, Xiaojun Xu, Maggie Liu, Gosia Nocula-Lugowska, Sam Stoner, Christopher Kraser, Ioanna Cheronis, Maria Delioukina, Lee Clark, Raj Bhadra, Murali Gururajan. Establishing a reverse translational platform to dissect mode of action and mechanisms of resistance to GUCY2C-CD3 T cell engager [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 6357.
Abstract 6364: The bispecific antibody KA-3006 against both EGFR and MET surpasses amivantamab in efficacy
Authors: Guojin Wu, Jiabei Liang, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning
Journal: Cancer Research (2024)

Abstract A bispecific antibody (BsAb) like amivantamab, which targets both the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) by blocking downstream pathways, has been proven to overcome resistance to targeted therapies, including EGFR inhibitors, in patients with various cancers. In this study, we developed a bispecific antibody, KA-3006, targeting both EGFR and MET using our common light chain antibody discovery platform. KA-3006 has a regular antibody structure with an identical light chain, developed through knob-into-hole technology. It exhibits high affinity for MET and relatively low affinity for EGFR. KA-3006 specifically blocks both the binding of EGF to EGFR and HGF to MET with higher efficiency than amivantamab, resulting in the blockade of downstream signaling from EGFR and MET. In comparison to amivantamab, KA-3006 demonstrates a faster internalization rate when binding to the surface of tumor cells expressing both EGFR and MET. KA-3006 showed superior antitumor activity over amivantamab in the HCC827-HGF in vivo model. Additionally, KA-3006 has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this BsAb with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, and KA-3006 showed neither aggregation nor degradation. In conclusion, the BsAb KA-3006, developed with our common light chain antibody discovery platform, is a promising pre-clinical candidate drug for the treatment of various solid cancers with overactivated EGFR and MET signaling, and it holds potential for developing ADCs targeting both EGFR and MET. Citation Format: Guojin Wu, Jiabei Liang, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning. The bispecific antibody KA-3006 against both EGFR and MET surpasses amivantamab in efficacy [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 6364.
Abstract 5872: CDK1-SOX9 axis contributes to chemotherapy resistance in gastric cancer
Authors: Marwah M. Al-Mathkour, Shoumin Zhu, Melanie Genoula, Wael El-Rifai
Journal: Cancer Research (2024)

Abstract Gastric carcinoma (GC) is the third most prevalent cause of cancer-related mortality worldwide, presenting a formidable challenge with the rise of resistance to chemotherapeutic agents, leading to treatment failures. Cyclin-dependent kinase 1 (CDK1) has garnered attention due to its substantial overexpression in various tumors, including GC, and its association with poor overall survival and relapse-free survival. This study aimed to understand the molecular and functional mechanisms underlying the CDK1-SOX9 axis in GC chemotherapy resistance. Through a comprehensive analysis of data from The Cancer Genome Atlas (TCGA) and our own integrated gene expression study, we found a positive correlation between CDK1 and SOX9 in both human and mouse GC tissues (p&amp;lt;0.001). Additionally, conserved alterations in miRNAs have been identified in the context of gastric carcinogenesis, evident in our local cohort and the TCGA dataset. Our in-depth investigation of premiR-145 has shed light on the existence of several CpG nucleotides. Notably, treatment with a DNMT inhibitor (5-Aza) has triggered the upregulation of miR-145 expression. Furthermore, the ectopic expression of CDK1 has been associated with increased DNMT1 phosphorylation and enhanced enzymatic activity. Conversely, silencing CDK1 reversed this effect, and the inhibition of DNMT1 reduced SOX9 protein expression. Using cisplatin-resistant cell lines revealed a significant increase in CDK1 and SOX9 expression where silencing CDK1 and SOX9 sensitized these cells to chemotherapy. This study provides valuable insights into the intricate mechanisms governing the CDK1-SOX9 axis in GC chemotherapy resistance, providing potential avenues for therapeutic interventions in this challenging malignancy. Citation Format: Marwah M. Al-Mathkour, Shoumin Zhu, Melanie Genoula, Wael El-Rifai. CDK1-SOX9 axis contributes to chemotherapy resistance in gastric 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 5872.
Abstract 5928: Structure-activity relationships for the pan-quadruplex experimental drug QN-302 and two analogs probed with comparative transcriptome profiling and molecular modeling
Authors: Ahmed A. Ahmed, Shozeb Haider, Tariq Arshad, Stephen Neidle
Journal: Cancer Research (2024)

Abstract The tetrasubstituted naphthalene diimide compound QN-302 binds to G-quadruplex DNA structures. It inhibits the transcription of cancer-related genes in pancreatic ductal adenocarcinoma (PDAC) cells, shows high potency in PDAC cells in vitro and in PDAC animal models. It is currently in Phase 1 clinical evaluation as an anticancer drug for advanced, metastatic solid tumors. A study of structure-activity relationships of QN-302 and two related analogs (CM03 and SOP1247) is reported here. These have been probed using comparisons of transcriptional profiles from whole-genome RNA-seq analyses, together with qualitative molecular modelling. Compounds CM03 and SOP1247 differ by the presence of a methoxy substituent in the former: these two have closely similar transcriptional profiles, whereas that of QN-302, although showing effects in the same cancer-related pathways, highlights the down regulation of distinct genes, for example in the hedgehog pathway. The distinct pattern of genes affected by QN-302 is hypothesized to contribute to its superior potency compared to CM03 and SOP1247. Its superior ability to stabilize quadruplex structures has been attributed to its benzyl-pyrrolidine substituent fitting into and filling most of the space in a quadruplex groove compared to the hydrogen atom in CM03 or the methoxy group in SOP1247. Citation Format: Ahmed A. Ahmed, Shozeb Haider, Tariq Arshad, Stephen Neidle. Structure-activity relationships for the pan-quadruplex experimental drug QN-302 and two analogs probed with comparative transcriptome profiling and molecular modeling [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 5928.
Abstract 5914: Non-muscle myosin IIA as a promising therapeutic target in breast cancer
Authors: Wasim Feroz, Rosalin Mishra, Mary Kate Kilroy, Joan T. Garrett
Journal: Cancer Research (2024)

Abstract We aimed to determine the role of non-muscle myosin IIA (NMIIA) in breast cancer using various cancer cell lines including estrogen receptor (ER)+, HER2+ and triple negative breast cancers (TNBC). Myosin heavy chain 9 (MYH9) gene encodes for the heavy chain of the hexameric protein NMIIA. We have recently identified that NMIIA serves as a binding partner for HER3 following the inhibition of the HER family member compared to the vehicle control treatment, as observed in HER3 immunoprecipitates. We checked the basal protein and mRNA levels of NMIIA in different breast cancer cell lines and found higher levels of NMIIA in both HER2+ and TNBC cell lines compared to ER+ cell lines. These data correlate with clinical data of primary breast cancer patients with high MYH9 being less likely in ER+ breast cancer patients and more likely in the PAM50 subtypes basal and HER2 enriched breast cancer patients. By employing a pool of four siRNA targeting MYH9, our data indicated a reduction in proliferation of HER2+ and TNBC cell lines when compared to the control siRNA. We have previously found that loss of MYH9 sensitizes to the HER family inhibitor neratinib treatment as assessed by cell proliferation, colony formation on matrigel, cell migration and invasion. We aimed to determine if pharmacological inhibition of the NMIIA pathway would sensitize to neratinib. RhoA-associated kinase (ROCK) serves as a master regulator of NMIIA activity as it directly phosphorylates the regulatory light chain (RLC) of NMIIA. Pharmacological inhibition of ROCK-NMIIA pathway using the ROCK inhibitor GSK269962A alone or in combination with neratinib reduced the cell proliferation in HER2+ cell lines BT474 and MDA-MB-453 as indicated by MTT and cell proliferation assay. It is well known that HER2-targeted therapies cause the upregulation of HER3. Given our identification of NMIIA as one of the interacting partners of HER3, our focus will be on investigating the NMIIA-HER3 signaling axis to elucidate its contribution to an adaptive response to HER2 inhibition and potential treatment resistance. Furthermore, we will explore strategies to target NMIIA in breast cancer. Citation Format: Wasim Feroz, Rosalin Mishra, Mary Kate Kilroy, Joan T. Garrett. Non-muscle myosin IIA as a promising therapeutic target in breast 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 5914.
Abstract 4808: Small intestinal leiomyosarcoma in a young adult
Authors: Alyssa A. Guo, Blake H. Bentley, Abigail L. Ellington, Haiyan Lu, William C. Lippert
Journal: Cancer Research (2024)

Abstract Objectives: • Outline the epidemiology of leiomyosarcoma•Identify the immunohistochemistry of a leiomyosarcoma Introduction: Primary small intestinal malignancies are rare malignancies as compared with other malignancies of the gastrointestinal tract. Here, we present a case of a jejunal leiomyosarcoma in a young adult. Case Presentation: A 23-year-old Caucasian male with GERD presented with five months of abdominal pain, intermittent nausea with non-bloody emesis, and a 20-pound weight loss. Presenting vital signs were within normal limits. Physical exam revealed conjunctival pallor with epigastric tenderness to palpation. Serology demonstrated iron deficiency anemia, hemoccult positive stool, negative CEA, CA19-9, and AFP tumor markers. HIV antigen antibody and EBV-PCR were non-reactive. CT of the abdomen and pelvis revealed markedly thickened heterogenous jejunal loop in the left hemiabdomen with associated mesenteric adenopathy and small volume pelvic ascites. EGD with push enteroscopy revealed a single, malignant appearing and ulcerated mass in the proximal jejunum. PET-CT showed a hypermetabolic, multilobulated, ill-defined mass involving multiple loops of jejunum. He underwent exploratory laparotomy with resection of a proximal jejunal mass (10x8 x7 cm), mesenteric lymphadenectomy, and a jejunojejunostomy creation. Pathology demonstrated leiomyosarcoma (pT2aN0MoG3), and he was initiated on cyclophosphamide and doxorubicin. Discussion: Primary small intestinal malignancies are rare malignancies with an incidence of less than 5% of all GI malignancies. 56 cases of GI leiomyosarcoma in adults were identified between 2000-2012 with a peak incidence between 55-59 years of age (Aggarrwal 2012). Leiomyosarcomas are soft tissue sarcomas arising from bones, tendons, blood vessels, or muscles with a spectrum of disease ranging from low-grade cutaneous lesions to aggressive lesions of internal organs with significant potential for metastasis (Pipe 2002). Diagnosis is based on immunohistochemical positivity for SMA, desmin, and h-caldesmon, and negativity for CD117, CD34, and DOG1.1, notably lacking KIT and PDGFRA mutations (Aggarwal 2012). Treatment involves surgical resection and a cost benefit analysis of adjuvant chemotherapy with (Reynolds, 2014). This case of a 23 year old, without significant risk factors, diagnosed with a jejunal leiomyosarcoma presents as one of the youngest cases ever to be reported and emphasizes the importance of recognizing the cancer in a broader range of the adult population. Citation Format: Alyssa A. Guo, Blake H. Bentley, Abigail L. Ellington, Haiyan Lu, William C. Lippert. Small intestinal leiomyosarcoma in a young adult [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 4808.