tbuckley/cabot-search huggingface dataset:
Abstract 835: A potent and selective small molecule inhibitor of CD38
Authors: Jinwen Huang, Zhongyuan Li, Zeng Song, Yunli Liu, Steve Shen
Journal: Cancer Research (2025)

Abstract Background: CD38 is a multifunctional ectoenzyme involved in NAD metabolism and is highly expressed in various hematological malignancies, making it a critical therapeutic target in oncology. By depleting NAD and producing immunosuppressive metabolites such as adenosine, CD38 supports tumor growth and creates an immunosuppressive microenvironment. Compared to CD38 antibodies, small-molecule inhibitor offer advantages, including better tissue penetration, oral bioavailability, and cost-effectiveness. CD38 inhibition may restore NAD levels, reverse immunosuppression, and enhance antitumor immune responses, potentially synergizing with immune checkpoint inhibitors (ICIs), providing a promising strategy for cancer therapy. Methods and Materials: Accelerated by the "Right 6D+AI" platform, AI-based screening and multi-angle evaluation were conducted on over 5, 000 virtual molecules, yielding candidate molecule N066 with IC50 activity below 1 nM. To explore the therapeutic potential, oral administration of N066 in mice assessed dose-dependent effects on NAD+ elevation and ADPR reduction in tissues such as the spleen and liver. In syngeneic cancer models, CD38 protein expression was evaluated using immunohistochemistry (IHC) following ICI treatment. In mouse solid tumor models, N066 was administered as monotherapy or combined with ICIs. Results: The small-molecule inhibited intracellular CD38 activity in cultured human primary T cells, increasing intracellular NAD+ levels. In mice, oral administration of the inhibitor resulted in a dose-dependent increase in NAD+ levels and a decrease in ADPR levels in tissues such as the spleen and liver. In syngeneic cancer models, monotherapy with the N066 showed antitumor activity correlated with changes in NAD+ and ADPR levels. In B16-F10 tumor-bearing mice, combining N066 with anti-PD-L1 therapy enhanced antitumor activity. Conclusion: CD38 small-molecule inhibitors N066 demonstrates good antitumor activity, highlighting its therapeutic potential. Citation Format: Jinwen Huang, Zhongyuan Li, Zeng Song, Yunli Liu, Steve Shen. A potent and selective small molecule inhibitor of CD38 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 835.
Abstract 983: Characterizing somatic copy number alterations in African American renal cell carcinoma patients
Authors: Musinu Zakari, Egbenoma A. Aigboeghian, Khadijah A. Mitchell
Journal: Cancer Research (2025)

Abstract Background: Renal cell carcinoma (RCC) has one of the highest mortality rates of all urologic cancers in the US. Somatic copy number alteration (SCNA) profiles have been linked with RCCC mortality. African American (AA) RCC patients have higher mortality and lower survival rates when compared to European Americans (EAs) with the disease. AA RCC patients are underrepresented in cancer genomic studies, and RCC mortality and survival disparities may be attributed to SCNA differences. We hypothesize there are distinct population-enriched SCNAs in RCC tumors from AAs compared with EAs. Methods: DNAs were isolated from fresh frozen primary tumors for each RCC patient in the Geisinger-Cooperative Human Tissue Network discovery cohort (n=20), followed by OncoScan CNV (whole-genome copy number microarray) analyses. SCNAs at the genome-wide, chromosomal, chromosomal region, and gene levels were compared in AA (n=10) and EA (n=10) RCC patients using Chromosome Analysis Suite v7. Population differences were calculated using t-tests with Welch’s corrections and multiple unpaired t-tests (P &amp;lt;0.05). STRING was used to identify protein-protein interaction networks and functional enrichment analyses. GraphPad Prism 10 v7 and STRING v12 were used to generate all images. Results: Genome-wide across 22 autosomes, a combined 397 chromosomal regions (n=292 amplifications; 105 deletions) were altered in AA RCC patients compared to 476 chromosomal regions (n=302 amplifications; 174 deletions) in EA RCC patients. We observed AAs had significantly higher amplifications across 13 chromosomes (3, 4, 6, 7, 9, 10, 13-15, 18, 20-22) when compared to their EA counterparts (P &amp;lt;0.05; AA: 164/292, EA: 156/302). A total of 12, 114 genes in AAs and 11, 320 genes in EAs were amplified. Uniquely amplified genes (n=1, 095) in AA RCC patients corresponded with keratin-associated protein (KRTAP) networks (PPI enrichment P value: 3.38e-08). EA RCC patients had 301 uniquely amplified genes that corresponded with trace-amine and natural killer cell lectin-like receptor activities (PPI enrichment P value: 0.000334). Conclusion: KRTAPs are known RCC oncogenes. KRTAP amplifications may drive expression and help to explain more aggressive tumor biology in AA RCC patients. Future Direction: Integrate SCNA data with matched bulk mRNA-sequencing data for each RCC patient. Citation Format: Musinu Zakari, Egbenoma A. Aigboeghian, Khadijah A. Mitchell. Characterizing somatic copy number alterations in African American renal cell carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 983.
Abstract 422: Aurora kinase A inhibition overcome adaptive resistance to KRAS G12C inhibitor by replication stress-induced genomic instability and mitotic cell death
Authors: Chendi Li, Varuna Nangia, Christopher J. Graser, Jeremy Chang, Anahita Nimbalkar, Mohammad U. Syed, Melissa Vieira, Yi Shen, Steve Altschuler, Lani Wu, Franziska Michor, Sabrina L. Spencer, Aaron N. Hata
Journal: Cancer Research (2025)

Cancer cells develop drug-tolerant states, enabling them to evade therapies. In response to KRAS G12C inhibitors (G12Ci), non-small cell lung cancer (NSCLC) cells harboring KRAS mutations sustain a drug-tolerant phenotype through the activation of aurora kinase A (AURKA). AURKA phosphorylates c-Raf, thereby sustaining KRAS signaling under G12Ci treatment. However, the molecular mechanism by which G12Ci treatment induces dependency on AURKA remains poorly understood, and there is currently a lack of molecular biomarkers that predict sensitivity to combined G12Ci and AURKA inhibitor (AURKAi) therapy. We show that the selective AURKAi (LSN3321213) induces mitotic catastrophe and subsequent cell death in NSCLC cells resistant to the G12Ci (LY3499446). Machine learning-based single-cell image tracking revealed that G12Ci-treated cancer cells overcome G1 arrest-induced apoptosis. When treated with AURKAi, these cells undergo mitotic stalling and subsequent mitotic slippage, allowing them to evade cell death. In contrast, simultaneous treatment with both inhibitors results in catastrophic mitotic cell death. G12Ci induces DNA damage as a result of replication stress, leading to increased apoptotic priming during mitosis, which may shift the cellular response towards mitotic catastrophe rather than slippage. Approximately 40% of genetic alterations in NSCLC are associated with replication stress, including MYC amplification. Our findings indicate that MYC amplification is associated with enhanced synergy between G12Ci and AURKAi in NSCLC. Furthermore, induction of CMYC expression in CMYC wild-type cell lines leads to mitotic catastrophe in response to G12Ci + AURKAi, suggesting that CMYC induces replication stress, thereby promoting a dependency on AURKAi. This study reveals a novel relationship between replication stress-induced genomic instability and mitotic defects in KRAS G12C NSCLC and identifies MYC amplification as a potential biomarker for guiding the selection of combined G12Ci and AURKAi therapy in patients with KRAS mutations and MYC amplification. Citation Format: Chendi Li, Varuna Nangia, Christopher J. Graser, Jeremy Chang, Anahita Nimbalkar, Mohammad U. Syed, Melissa Vieira, Yi Shen, Steve Altschuler, Lani Wu, Franziska Michor, Sabrina L. Spencer, Aaron N. Hata. Aurora kinase A inhibition overcome adaptive resistance to KRAS G12C inhibitor by replication stress-induced genomic instability and mitotic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 422.
Abstract 386: High CRBN expression in neuroendocrine cancer creates a vulnerability to GSPT1 molecular glue degraders: Target indication selection for CYRS1542 development
Authors: Jaewoo Park, Min Sung Joo, JaeYung Lee, Eun-Jung Kim, Dong Hyuk Ki, Hunmi Choi, Wooseok Han, Keon Wook Kang
Journal: Cancer Research (2025)

Abstract Multiple companies have been developing GSPT1-targeted molecular glue degraders (MGDs) for neuroendocrine (NE) cancers, a rare and aggressive cancer type. CYRS1542, a potent and orally bioavailable GSPT1 MGD with a superior therapeutic index, was identified and derived from CYRS381 (originally known as SJ6986) in our previous work (Joo et al., AACR 2024). In this study, we investigated the mechanistic basis of GSPT1 MGD sensitivity in NE cancers, using CYRS381 as a tool compound to assess selective susceptibilities. We found that CYRS381-induced GSPT1 degradation was selectively effective in the NE cancers with high CRBN expression, while the non-NE cancers with a low level of CRBN showed limited response. NE cancer cells positive for NE markers exhibited both higher CRBN expression and greater sensitivity to CYRS381, showing rapid GSPT1 degradation upon GSPT1 MGD treatment compared to non-NE cancer cells. Further analysis of TCGA and DepMap expression data revealed a significant positive correlation between high CRBN levels and NE characteristics, whereas GSPT1 levels showed no such correlation. Consistently, overexpressing CRBN in non-NE cancer cells increased sensitivity to GSPT1 MGD, and introducing NE-driving factors in non-NE cancer cells elevated CRBN expression, further enhancing the response to GSPT1 MGD. Finally, CYRS1542 demonstrated effects similar to CYRS381 in comparable experiments, further supporting the selection of NE cancers as the lead indication for its clinical trials. Overall, these findings highlight CRBN as a key determinant of GSPT1 MGD efficacy and underscore the potential of CYRS1542 as a targeted therapeutic option for aggressive NE cancers. Citation Format: Jaewoo Park, Min Sung Joo, JaeYung Lee, Eun-Jung Kim, Dong Hyuk Ki, Hunmi Choi, Wooseok Han, Keon Wook Kang. High CRBN expression in neuroendocrine cancer creates a vulnerability to GSPT1 molecular glue degraders: Target indication selection for CYRS1542 development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 386.
Abstract 373: Comparison of the anti-cancer mechanism of tolfenamic acid and its copper (II) complex
Authors: Hayden Flume, Riva Sarkar, Tanaya Washington, Ethan Schroeder, Sakariyau A. Waheed, Kaylin L. Thomas, Stephen Beebe, Riyaz Basha, Alvin Holder, Umesh T. Sankpal
Journal: Cancer Research (2025)

Abstract Tolfenamic acid (TA), a non-steroidal anti-inflammatory drug, has demonstrated anti-cancer properties across multiple cancer models including prostate, pancreatic, ovarian, colon, leukemia, lung, and medulloblastoma. Studies have identified potential targets of TA including transcription factors Sp1, Sp3 and Sp4, anti-apoptotic proteins survivin and Bcl2, anti-angiogenic protein VEGF, and NFkB gene products. These interactions result in inhibition of cell proliferation, induction of apoptosis, and suppression of tumor growth in mouse models. To enhance the efficacy of TA, a novel copper (II) complex of TA ([Cu(TA)2(bpy)], bpy = 2,2’-bipyridine, Cu(II)-TA) was synthesized. Cell viability assays revealed that Cu(II)-TA exhibited greater anti-proliferative activity than TA, as indicated by lower IC50 values. However, the mechanism underlying this increased activity remains unclear. In this study, we compared the mechanism of action of TA and Cu(II)-TA in medulloblastoma cells. The anti-proliferative activity of the two compounds was assessed using a cell viability assay and the apoptotic activity was evaluated by caspase 3/7 activity assay. Cell cycle effects were analyzed by flow cytometry and DNA damage was assessed by measuring levels of phospho-H2AX using western blot and immunofluorescence microscopy. Consistent with previous findings, we observed increased anti-proliferative effects with Cu(II)-TA compared to TA in medulloblastoma cells. This enhanced activity was accompanied by increased apoptosis as indicated by higher caspase 3/7 activity. Cell cycle analysis by flow cytometry revealed distinct profiles for the inhibitors. TA treatment resulted in increased G2/M population, while Cu(II)-TA did not show a prominent or dose-dependent increase with treatment. Interestingly, TA induced greater DNA damage than Cu(II)-TA as indicated by increased phospho-H2AX levels detected by western blotting and immunofluorescence staining. These findings suggest that while Cu(II) enhances the anti-proliferative activity of TA, the underlying mechanisms differ, likely involving distinct proteins and pathways. Citation Format: Hayden Flume, Riva Sarkar, Tanaya Washington, Ethan Schroeder, Sakariyau A. Waheed, Kaylin L. Thomas, Stephen Beebe, Riyaz Basha, Alvin Holder, Umesh T. Sankpal. Comparison of the anti-cancer mechanism of tolfenamic acid and its copper (II) complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 373.
Abstract 272: Loss of Rab25 and associated mechanisms in cancerous transformation of melanocytes
Authors: Samikshya Kandel, Krishna Rao
Journal: Cancer Research (2025)

Abstract Background: Rab25 is a member of RAS protein superfamily of small GTPases that belong to RAB11 subfamily located on 1q22 of chromosome. It is generally expressed by epithelial cells and its expression level varies by tissue types. From our previous research, Rab25 has been shown to be a significant player in moderating transformation of human mammary epithelial cells, as its loss promotes cellular transformation particularly in presence of RAS mutation. Rab25 is an ambiguous protein in cancer research as its role is cancer type dependent and remains unknown in melanoma. There is deep deletion of Rab25 in a section of melanomas (only∼3% profiled) in databases like the Cancer Genome Atlas and Cbioportal. Additionally, Rab25 shares a common consensus motif with the binding site of mutant H-RAS, Q61L. NRAS is mutated in 80% of RAS activated melanomas. Therefore, we are investigating the role of Rab25 loss in the development of NRAS mutant melanoma. Objectives: To study the status of Rab25 and its role in the transformation of melanocytes, we screened for Rab25 expression and protein level in different melanoma cell lines. We further did immunohistochemistry to examine the Rab25 expression in biopsy-proven melanoma sections. To uncover the function of Rab25, we overexpressed Rab25 in NRAS mutant melanoma cell lines and knocked down Rab25 in non-tumorigenic immortalized melanocytes. Further, we will use liposomal encapsulation technique to deliver a six-peptide sequence intracellularly to target NRAS. Results: There was significant loss of Rab25 in mRNA and protein level in melanoma cell lines. Rab25 is found in normal skin tissues but was significantly lost in melanoma sections and associated with reduced survival. NRAS mutant human melanoma cells transduced with Rab25 showed reduced proliferation, migration tendency, and loss of anchorage-independence growth as compared to control cell lines. Additionally, knockdown of Rab25 in non-cancerous immortalized human melanocytes showed resulted in enhanced proliferative behavior and gain of anchorage-independent growth in soft agar colony formation assay. Conclusion: These observations suggest that Rab25 loss results in gain of migratory potential, anchorage-independent growth, and enhanced proliferation potential which are requisite events in melanoma-genesis. Further studies on associated functional proteins of Rab GTPase family will be conducted to strengthen this data. Citation Format: Samikshya Kandel, Krishna Rao. Loss of Rab25 and associated mechanisms in cancerous transformation of melanocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 272.
Abstract 387: Preclinical biological screening and evaluation of KRAS molecular glues
Authors: Zhaoxia Yin, Lili Chai, Xian Wu, Tao Li, Xiaojian Wang, Tj (Tiejun) Bing
Journal: Cancer Research (2025)

Abstract The KRAS protein is a signal transduction molecule associated with various types of cancer. Due to its high mutation rate and key role in tumor development, KRAS has become an important target for anti-cancer drug development. Activating mutations in KRAS, such as KRASG12C, are prevalent in about one-third of all human cancers and significantly contribute to tumor initiation, progression, and resistance to therapy. In recent years, with the continuous deepening of research related to KRAS, a new therapeutic strategy targeting the KRAS protein has been discovered, known as KRAS molecular glue. KRAS molecular glue specifically binds to particular mutation sites on the KRAS protein, such as the G12C mutation, thereby preventing its interaction with downstream signaling molecules and inhibiting the proliferation and survival of tumor cells. In this context, we have developed a comprehensive screening and evaluation platform for KRAS molecular glue, covering studies from in vitro to in vivo. The platform includes a series of assays at both the biochemical and cellular levels. It utilizes biochemical and biophysical methods for the screening of POI binders, detection of KRAS(ON)/CypA/cRAF binary complexes, and KRAS(ON)/CypA ternary complexes, among others. Cell-based functional assays such as 3D cell proliferation and detection of ERK phosphorylation, a marker related to signaling pathways, are also included. Additionally, we offer p-ERK panel and 2D/3D cell panel including pan KRAS cell panel, KRAS G12D cell panel, KRAS G12C cell panel, KRAS G12V cell panel, pan NRAS cell panel and pan HRAS cell panel tests for KRAS molecular glue, and we can also supply KRAS G12C mutation-resistant cell lines for related testing. Of course, it also includes the efficacy assessment of the CDX model in vivo. Overall, we provide a comprehensive platform for the screening and evaluation of KRAS molecular glue, offering a scientific basis for the clinical application of KRAS molecular glue. Citation Format: Zhaoxia Yin, Lili Chai, Xian Wu, Tao Li, Xiaojian Wang, Tj (Tiejun) Bing. Preclinical biological screening and evaluation of KRAS molecular glues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 387.
Abstract 616: TYK2: A novel therapeutic target in triple-negative breast cancer brain metastasis
Authors: Jayshree Mishra, Priyam Kumar, Narendra Kumar
Journal: Cancer Research (2025)

Breast cancer (BC) is one of the deadliest cancers that affect 300,000 women annually where 15-25% are Triple negative in nature and spreads quickly to the brain causing brain metastasis (TNBC-BM). Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by lack of hormone receptor expression and is known for high rates of recurrence, distant metastases, and poor clinical outcomes. The 5-year survival rate for TNBC-BM is only 9%. Current standard of care to treat TNBC-BM include whole brain radiation therapy, surgery and chemotherapy which leads to sever side effects, high level of neurotoxicity, neurological complication that leads to low survival rate and low quality of life. Because of such a low survival rate, there is an unmet clinical need to treat these patients differently to decrease neurotoxicity, and TNBC-BM cell death. In our study, we identified and characterized novel therapeutic targets and targeted pharmacologic inhibitors of natural compound origin for the treatment of TNBC-BM. Our preliminary data suggest (1) overexpression of Tyk2 ( JAK Family meber) gene in TNBC-BM compared to TNBC and TNBC lung metastasis using a PDX database. Overall Survival analysis of TNBC patients databases suggest that higher expression of Tyk2 gene and it’s downstream signaling partner gene STAT5A. Tyk2 is overexpressed in the TNBC-BM metastatic brain sample and TNBC -BM specific cell line ( BrM-831). Based on the published literature and our strong preliminary data, we hypothesize that over expression of Tyk2 promotes brain metastasis in TNBC cells through the activation of Tyk2-STA5A signaling pathway stimulating epithelial-to-mesenchymal transition, cell migration and invasion of TNBC cells, leading to tumorigenesis and metastasis in TNBC; Together, this study will demonstrate Tyk2 as a new target and Tyk2 targeted therapeutic agent will be capable of inhibiting TNBC-metastasis through blocking the activation of the Tyk2-/STAT5 molecular targets. In future, we plan to develop Tyk2 targeted drug compounds originated from natural products to treat TNBC-BM. Citation Format: Jayshree Mishra, Priyam Kumar, Narendra Kumar. TYK2: A novel therapeutic target in triple-negative breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 616.