tbuckley/cabot-search huggingface dataset:
Abstract CT216: Anti-EGFR in combination with paclitaxel as second-line therapy for gastric cancer with EGFR overexpression
Authors: Dong-Hoe Koo, Jin-Young Kim, Jae-Joon Kim, Sung Y. Oh, Min-Hee Ryu, Dae Y. Zang, Hark K. Kim
Journal: Cancer Research (2024)

Abstract Background: We and other investigators reported that EGFR gene is amplified in 2-4% of gastric cancer with protein overexpression (Gastroenterology 2017 Aug;153(2):536-549; Cancer Cell 2019 Jan 14; 35:1:111:E10), but EGFR-targeted therapy has not entered into clinic. Patients and Methods: As a subprotocol of the investigator-initated of umbrella trial, patients with metastatic gastric cancer received weekly anti-EGFR monoclonal antibody (GC-1118 (GC Biopharma), 2.5mg/kg) in combination with paclitaxel 80mg/m2 (D1, D8, D15) every 4 weeks as a second-line therapy, if the gastric cancer tissue sample revealed EGFR protein overexpression (NCT04077255). Projected accrual was 19 based on minimax two-stage design (P1=45%; P0=15%; alpha and beta errors, 0.05 and 0.1, respectively). Results: Among 19 evaluable patients, 6 patients had objective clinical response (RR, 31.6%). Median progression-free survival was 4.7 months (95% CI, 1.8-5.1). Median overall survival was 7.6 months (95% CI, 4.2-11.1). Predictive biomarkers were explored by post hoc correlative analyses. Conclusion: EGFR inhibition, in combination with paclitaxel, demonstrated modest activity for gastric cancer refractory to first-line 5-FU/platinum-based chemotherapy. (This study was supported by a grant from the National R&amp;D Program for Cancer Control, Ministry of Health &amp; Welfare, Republic of Korea (HA22C0056.)) Citation Format: Dong-Hoe Koo, Jin-Young Kim, Jae-Joon Kim, Sung Y. Oh, Min-Hee Ryu, Dae Y. Zang, Hark K. Kim. Anti-EGFR in combination with paclitaxel as second-line therapy for gastric cancer with EGFR overexpression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT216.
Abstract CT221: Belzutifan, a hypoxia-inducible factor-2α (HIF-2α) inhibitor, for von Hippel-Lindau (VHL) disease-associated neoplasms: Long-term results of the phase 2 LITESPARK-004 study
Authors: Ramaprasad Srinivasan, Othon Iliopoulos, Kathryn E. Beckermann, Vivek Narayan, Benjamin L. Maughan, Stephane Oudard, Tobias Else, Jodi K. Maranchie, Ane B. Iversen, Jerry Cornell, Rodolfo F. Perini, Yanfang Liu, W. Marston Linehan, Eric Jonasch
Journal: Cancer Research (2024)

Abstract Introduction: Belzutifan is a first-in-class HIF-2α inhibitor approved for patients (pts) with VHL disease-associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas (HB), or pancreatic neuroendocrine tumors (pNET) not requiring immediate surgery based on initial results from the phase 2 LITESPARK-004 study (NCT03401788). We present results from pts with more than 4 years of follow-up from LITESPARK-004. Methods: Adults with germline VHL alteration, ≥1 measurable nonmetastatic RCC tumor, no RCC tumor &amp;gt;3 cm requiring immediate surgery, and no prior systemic anticancer therapy received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR) in VHL-associated RCC per RECIST v1.1 by independent review. Secondary end points included ORR in CNS HB and pNET; duration of response (DOR), time to response (TTR), progression-free survival (PFS), and time to surgery (TTS) in RCC, CNS HB, and pNET; and safety. Results: As of April 3, 2023, 36 of 61 pts (59%) were continuing treatment. Median follow-up was 49.9 mo (range, 48.2-58.1). Efficacy data are shown in the table. In the 4 years preceding belzutifan treatment, 46 pts (75%) underwent a total of 86 VHL-related tumor reduction procedures (surgery or radiation therapy). Since starting belzutifan, 16 pts (26%) underwent 18 tumor reduction procedures (RCC, n = 13; CNS HB, n = 3; retinal HB, n = 2). Safety profile remained unchanged with long-term follow-up. Conclusions: With a median follow-up of more than 4 years, belzutifan continues to demonstrate clinically meaningful ORR and durable responses in VHL-associated RCC, CNS HBs, and pNET. Fewer tumor reduction procedures were observed after pts started belzutifan treatment. These results support belzutifan as a standard of care for this pt population. Citation Format: Ramaprasad Srinivasan, Othon Iliopoulos, Kathryn E. Beckermann, Vivek Narayan, Benjamin L. Maughan, Stephane Oudard, Tobias Else, Jodi K. Maranchie, Ane B. Iversen, Jerry Cornell, Rodolfo F. Perini, Yanfang Liu, W. Marston Linehan, Eric Jonasch. Belzutifan, a hypoxia-inducible factor-2α (HIF-2α) inhibitor, for von Hippel-Lindau (VHL) disease-associated neoplasms: Long-term results of the phase 2 LITESPARK-004 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT221.
Abstract LB022: Preclinical anti-tumorigenic evaluation of AXL targeting antibody-drug-conjugate in an adenoid cystic carcinoma cell line xenograft model
Authors: Joseph O. Humtsoe, Anita Pothukuchi, Hyunseok Kang, Patrick Ha
Journal: Cancer Research (2024)

Abstract Adenoid cystic carcinoma (ACC) is a rare type of salivary gland cancer. Despite the many advances made in helping understand the disease behavior and characteristics, the prevailing challenge in managing patients with ACC is the lack of clinically approved systemic therapy drugs to successfully treat those with advanced recurrent or metastatic disease. There are multiple promising candidate agents being evaluated preclinically and in early phase clinical trials, yet an effective drug with consistent overall response remains to be identified. AXL is a member of the TAM family of tyrosine kinase receptors, and its overexpression and activation is generally associated with poor prognosis and chemoresistance in many cancer types. Previous reports show AXL is significantly upregulated in a subset of ACC tumors. Here, we evaluate the tumor growth inhibition effects of a newly developed antibody-drug-conjugate targeting AXL (ADCT-601) in a xenograft ACC cell line model. MDA-ACC-01 cells express high levels of cell surface AXL as confirmed by biochemical analysis. The tumor growth inhibition of MDA-ACC-01 cell xenograft was tested in a single-dose drug administration study. Immunodeficient mice bearing ACC tumors were either injected with vehicle (n=7) or with ADCT-601 at 0.5 (n=9) or 1.0 mg/kg (n=7). ADCT-601 treatment with either 0.5 mg/kg or 1.0 mg/kg resulted in complete response (CR) for all tumor implants. To reaffirm the drug’s efficacy, we challenged the vehicle-treated tumor, prior to exceeding the tumor volume endpoint, with a single-dose of ADCT-601 at 1.0 mg/kg. Strikingly, by day 6 post-treatment, tumor volume began to shrink and eventually resulted in CR except in all but one case. These results demonstrate ADCT-601 is an effective drug with significant anti-tumor activity in our preclinical models and is worthy of additional investigation to determine its translational potential. Citation Format: Joseph O. Humtsoe, Anita Pothukuchi, Hyunseok Kang, Patrick Ha. Preclinical anti-tumorigenic evaluation of AXL targeting antibody-drug-conjugate in an adenoid cystic carcinoma cell line xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB022.
Abstract LB164: Inducing immunogenic cell death in difficult-to-treat cancers with an orally-bioavailable GPX4 inhibitor
Authors: Timothy J. Read, Richard Steel, Ardeshir Golialei, Jenna Rimel, Leah Damon, Joey Azofeifa
Journal: Cancer Research (2024)

Abstract Recent advancements in immunotherapy have transformed cancer treatment, resulting in extended survival times for some patients. However, despite these advancements, many patients do not benefit from immunotherapy because of an immunosuppressive tumor microenvironment. Consequently, there is a need for new strategies to improve the effectiveness of immunotherapy by stimulating inflammatory immunogenic cell death in tumors. Ferroptosis is a recently-described form of non-apoptotic cell death that induces a uniquely inflammatory immunogenic cell death. Glutathione Peroxidase 4 (GPX4) is the cell’s major defense system against ferroptosis as it is the only known enzyme capable of reducing toxic lipid hydroperoxides to inert lipid alcohols. Here we describe the discovery of a series of potent and selective small molecule GPX4 inhibitors that result in significant tumor growth inhibition in several aggressive tumor CDX models. We verified induction of ferroptosis in tumors using known biomarkers of ferroptosis such as HMOX1 mRNA induction as well as with 4-HNE staining. GPX4 target engagement and degradation was confirmed by mass spectrometry and western blot in tumors. GPX4 inhibition, when combined with PDL-1 blockade in a syngeneic sarcoma model, resulted in sustained significant tumor growth inhibition throughout the course of a 28-day study at well-tolerated doses when compared to either monotherapy alone. Current studies are underway to more carefully define the unique immunogenic cell death imparted by GPX4 inhibition and resulting ferroptosis. Citation Format: Timothy J. Read, Richard Steel, Ardeshir Golialei, Jenna Rimel, Leah Damon, Joey Azofeifa. Inducing immunogenic cell death in difficult-to-treat cancers with an orally-bioavailable GPX4 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB164.
Abstract LB159: Discovery of HP560, a novel BET inhibitor for the treatment of myelofibrosis
Authors: Jing Li, Lei Fan, Hongwei Yuan, Yongxu Huo, Hua Yu, Fei Wang, Xinghai Li
Journal: Cancer Research (2024)

Abstract Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by defective clonal hematopoiesis, bone marrow fibrosis, splenomegaly, severe anemia, and the propensity for transformation to acute myeloid leukemia (AML). Inhibitors targeting JAKs (Janus kinases) have revolutionized the treatment of MF, but are limited by modest efficacy or acquired resistance after prolonged treatment. Here, we report a novel inhibitor, HP560 that targets BET (bromodomain and extra-terminal) proteins and shows promising therapeutic activities against MF and AML. Through engaging the bromodomain pocket of BET proteins in a competitive manner with acetylated histones, HP560 causes the disruption of BET proteins from chromatin. HP560 has high binding affinities for all BET proteins and strong anti-proliferative activity as well as synergistic anti-proliferative effect in combination with ruxolitinib, a JAK1/2 inhibitor. In an MF cell line derived tumor xenograft (CDX) mouse model, HP560 prolongs survival and improves splenomegaly and anemia, and these effects are enhanced when combined with ruxolitinib. HP560 also significantly and dose-dependently inhibits tumor growth in an AML CDX mouse model. Together, HP560 is a potent pan-BET inhibitor and can be developed as a monotherapy or in combination with a JAK inhibitor for the treatment of MF. HP560 structure will not be disclosed. Citation Format: Jing Li, Lei Fan, Hongwei Yuan, Yongxu Huo, Hua Yu, Fei Wang, Xinghai Li. Discovery of HP560, a novel BET inhibitor for the treatment of myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB159.
Abstract LB050: BRAF V600E is associated with the upregulation of CLDN1 in thyroid cancer
Authors: Andrea Ross Orozco, Eliakym Arámbula Meraz, Anette Roxana Gastelum Quiroz, Fred Luque Ortega, Edith Eunice García Alvarez, Marco Álvarez Arrazola, Karla Lizbeth Morales Hernández, Noemí García Magallanes
Journal: Cancer Research (2024)

Abstract Thyroid carcinoma is the most prevalent endocrine neoplasm. The most recurrent mutation in thyroid cancer (TC) is the V600E substitution in BRAF, which induces the over-activation of the MAPK pathway. The interaction between this pathway and the deregulation of genes that facilitate tumorigenesis such as CLDN1 could be useful for decision-making related to surgical removal and the degree of initial resection; however, there is a lack of information on the association of CLDN1 expression with BRAF V600E. Objective. Evaluate the gene expression of CLDN1 in BRAF-mutated and BRAF-unmutated thyroid nodules. Methods. RT-qPCR was performed to assess BRAF genotyping (rs113488022) and CLDN1 expression in 94 thyroid nodule biopsy samples (TC=48). Clinicopathological data was retrieved to establish further associations. Results. Mutated BRAF thyroid nodules were found to be 7.14 ± 0.293 times more expressed than those without the mutation (p &amp;lt 0.001, N=94). BRAF V600E mutation was identified in patients with TC exclusively. CLDN1 expression was 41.315 ± 0.554 times greater in patients with TC than in those without TC (p &amp;lt 0.001). Heterozygous patients had a change factor of 6.8, whereas mutated homozygotes had a change factor of 7.5 (p &amp;lt 0.001, N=94). CLDN1 mean expression is significantly higher in A allele carriers compared to normal homozygotes (p &amp;lt 0.001). When analyzing just within the TC group, the behavior is maintained, suggesting a potential association between the mutated allele and the expression of these genes. Conclusion. CLDN1 is significantly upregulated in TC patients carrying the BRAF V600E mutation. BRAF V600E is only observed in patients with TC, implying a biological connection between them, which can be explained via MAPK; subsequent studies are needed to confirm the correlations. Citation Format: Andrea Ross Orozco, Eliakym Arámbula Meraz, Anette Roxana Gastelum Quiroz, Fred Luque Ortega, Edith Eunice García Alvarez, Marco Álvarez Arrazola, Karla Lizbeth Morales Hernández, Noemí García Magallanes. BRAF V600E is associated with the upregulation of CLDN1 in thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB050.
Abstract ND10: NST-628 is a novel, potent, fully brain-penetrant MAPK pathway molecular glue that inhibits RAS- and RAF-driven cancers
Authors: Meagan B. Ryan, Bradley Quade, Natasha Schenk, Zhong Fang, Marshall Zingg, Steven E. Cohen, Chun Li, Brooke M. Swalm, Aysegul Ozen, Chaoyang Ye, Maria Stella Ritorto, Xin Huang, Arvin C. Dar, Yongxin Han, Michael Hale, Margit Hagel, Klaus P. Hoeflich
Journal: Cancer Research (2024)

Abstract Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are drivers for many cancers. Apart from approved mutation-selective inhibitors for BRAF Class I and KRAS G12C mutations, other mutations of RAS and RAF are not directly addressable by currently approved inhibitors and there is a need for therapeutic strategies having superior efficacy, durability and tolerability for the MAPK pathway. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF. In this way, NST-628 overcomes the limitations of traditional RAS-MAPK inhibitors and drives deep, durable inhibition of the RAS-MAPK pathway. Cellular, biochemical, and structural analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF and BRAF-ARAF heterodimers, a differentiated mechanism from all current RAF-directed inhibitors. With its potent and durable inhibition of the RAF-MEK signaling complex, NST-628 demonstrates broad efficacy in cellular and patient-derived, in vivo tumor models harboring KRAS, NRAS, BRAF class II/III, and NF1 mutations. In addition, high intrinsic permeability across the blood-brain-barrier results in NST-628-mediated intracranial anti-tumor activity in orthotopic tumor models. Furthermore, NST-628 pharmacokinetic and metabolic profiles have been optimized for daily dosing in the clinic to maximize therapeutic index. Given its differentiated molecular mechanism, best-in-class drug-like properties, and superior safety profile in IND-enabling GLP studies, NST-628 is positioned to make an impact clinically to address unmet patient need. First-in-human trials of NST-628 have been initiated in early 2024 Citation Format: Meagan B. Ryan, Bradley Quade, Natasha Schenk, Zhong Fang, Marshall Zingg, Steven E. Cohen, Chun Li, Brooke M. Swalm, Aysegul Ozen, Chaoyang Ye, Maria Stella Ritorto, Xin Huang, Arvin C. Dar, Yongxin Han, Michael Hale, Margit Hagel, Klaus P. Hoeflich. NST-628 is a novel, potent, fully brain-penetrant MAPK pathway molecular glue that inhibits RAS- and RAF-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND10.
Abstract PL03-02: From microniches to single cells: Understanding the impact of intratumoral microbes on spatial and cellular heterogeneity in cancer
Authors: Susan Bullman
Journal: Cancer Research (2024)

Abstract The tumor microenvironment (TME) is a dynamic network that includes a variety of non-malignant cells such as endothelial cells, fibroblasts, and immune cells, which play a crucial role in tumor behavior. Advances in molecular analysis have recently identified the presence of intratumoral microbiota in several solid cancer types. However, the specific ways these microorganisms interact with human cells within the TME and contribute to disease progression are not yet fully understood. Our recent research provides new insights into how bacterial components of the intratumoral microbiota contribute to tumor heterogeneity, particularly in head and neck and colorectal cancers. To investigate these interactions, we have adapted and applied emerging technologies in spatial transcriptomics, spatial proteomics, and single-cell sequencing (INVADEseq). Our spatial analyses show that the intratumoral microbiota are not distributed randomly within human tumors; instead, they localize to distinct microniches that promote immune and epithelial cell functions supportive of cancer progression. These bacterial-colonized microniches are characterized by myeloid cell infiltration, upregulation of MAPKs and immune checkpoint proteins, and reduced T-cell levels. Furthermore, INVADEseq single-cell RNA sequencing has enabled us to identify the dominant host cell-associated bacteria, the human cell types they infect, and their impact on the transcriptional programs of infected cells from patient tumor specimens. In oral squamous cell carcinoma, Fusobacterium and Treponema species have been identified as the dominant cell-associated bacterial taxa, primarily infecting subsets of macrophages and aneuploid cancer epithelial cells and upregulating pathways associated with cancer progression. Our findings offer insights into the complex interplay between intratumoral microbiota and human components of the TME, emphasizing their role in supporting intratumoral heterogeneity and influencing cancer progression. Understanding these dynamics holds significant promise for the development of targeted therapeutic strategies aimed at disrupting bacterial-human spatial and cellular interactions within the TME. Citation Format: Susan Bullman. From microniches to single cells: Understanding the impact of intratumoral microbes on spatial and cellular heterogeneity in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr PL03-02.
Abstract CT217: First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b-2 trial
Authors: Marion Thibaudin, Jean-David Fumet, Emeric Limagne, Léa Hampe, Susy Daumoine, Valentin Derangère, Caroline Laheurte, Olivier Adotevi, Caroline Truntzer, François Ghiringhelli
Journal: Cancer Research (2024)

Abstract Metastatic colorectal cancer (mCRC) remains a difficult-to-treat disease. While patients with microsatellite instable metastatic colorectal cancer (mCRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single arm, phase IB/II MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable mCRC. Safety was the primary objective of phase IB; no safety issue was observed. The phase II primary objective of efficacy in terms of 3-month PFS in MSS patients was met, with 3-month PFS of 90.7% [95% CI: 79.2-96%]. For secondary objectives, response rate was 64.5%, median PFS was 8.2 months [95% CI: 5.9-8.6] and overall survival was not reached in MSS patients. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature, and low epithelio-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor specific T cell response, associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758. Citation Format: Marion Thibaudin, Jean-David Fumet, Emeric Limagne, Léa Hampe, Susy Daumoine, Valentin Derangère, Caroline Laheurte, Olivier Adotevi, Caroline Truntzer, François Ghiringhelli. First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b-2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT217.