tbuckley/cabot-search huggingface dataset:
Abstract 3273: Tirapazamine sensitizes homologous recombination-proficient cancers by enhancing DNA damage andferroptosis
Authors: Yanyan Jiang, Hala Estephan, Yizhou Wang, Ftoon Aljarbou, Nuria V. Lopera, Eui Jung Moon, Ester M. Hammond, Amato J. Giaccia
Journal: Cancer Research (2024)

Abstract Despite its success in HR-deficient tumors, the application of PARP inhibitors (PARPis) in HR-proficient cancers is very limited. Since the majority of cancers are HR-proficient, there is a need for developing strategies to extend the use of PARPis to HR-proficient cancers. We investigated whether the hypoxic cytotoxin, tirapazamine (TPZ) sensitizes HR-proficient cancer cells to PARPis under normoxia and hypoxia (2% O2), and found that TPZ enhanced PARPi cell killing to a greater extent under hypoxia compared to normoxia. Mechanistically, this enhanced killing was due to the induction of DNA double-strand breaks and free radicals that lead to ferroptotic cell death. To determine the role of hypoxia in the anti-tumor effect of the combination treatment, we examined the efficacy of TPZ and PARPi treatment in hypoxic spheroids and subcutaneous xenograft models derived from a panel of HR-proficient human non-small cell lung cancer (NSCLC) cells. We found that PARPis combined with TPZ significantly inhibited the growth of the hypoxic NSCLC spheroids. In addition, the combination treatment significantly inhibited the growth of A549 and CORL105 xenografts that possess significant hypoxic fractions, but did not significantly inhibit the growth of well-oxygenated Calu3 and H3122 xenografts. Taken together, this study demonstrates that TPZ can sensitize HR-proficient tumor cells to PARPi through the introduction of DNA strand breaks and free radicals, suggesting that TPZ treatment can broaden the usage of PARPi to HR-proficient cancers. Citation Format: Yanyan Jiang, Hala Estephan, Yizhou Wang, Ftoon Aljarbou, Nuria V. Lopera, Eui Jung Moon, Ester M. Hammond, Amato J. Giaccia. Tirapazamine sensitizes homologous recombination-proficient cancers by enhancing DNA damage andferroptosis [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 3273.
Abstract 5533: The difference of immune microenvironment between<i>de novo</i>metastatic and non-metastatic microsatellite instability-high colorectal cancer
Authors: Kuo-Hsing Chen, Chia-Lang u Hs, Yu-Li Su, Chang-Tsu Yuan, Jia-Huei Tsai, Yi-Hsin Liang, Ann-Lii Cheng, Kun-Huei Yeh
Journal: Cancer Research (2024)

Abstract Introduction: Microsatellite instability-high (MSI-H) colorectal cancer (CRC) consists of 15% of all CRC but only 2-4% of metastatic CRC. The favorable prognosis of non-metastatic (early-stage) MSI-H CRC may be related to vigorous immune reaction in tumor microenvironment. However, the mechanisms of immune evasion in metastatic (late stage) MSI-H CRC are largely unknown. Materials and Methods: We retrospectively collected patients with MSI-H CRC from National Taiwan University Hospital and Kaohsiung Chang Gung Memorial Hospital. The archival tumor specimens were used for immune cells analysis by Nanostring PanCancer Immune Panel, and spatial immune characterization by multiplex immunofluorescence stains. Only surgical resected primary tumors and metastatic tumors were included. Gene expression and immune cells composition were compared between non-metastatic and de novo metastatic tumors. Results: We enrolled 59 and 27 patients with early-stage and late-stage MSI-H CRC, respectively. Twelve metastatic site tumors were also collected. The clinicopathologic characteristics between patients who have early- and late-stage MSI-H CRC were not significantly different. There are heterogeneous immune cell compositions in these 98 MSI-H tumors. Compared to early-stage MSI-H tumors, there are significantly fewer cytotoxic (difference -0.497, p = 0.001) and dendritic cells (difference -0.528, p = 0.021) in late-stage MSI-H tumors. Gene set enrichment analysis disclosed significantly decrease in the expression of JAK-STAT-IFN-γ- and antigen processing-related pathways in late-stage MSI-H tumors. The top 5 genes with significantly differential expression between late-stage and early-stage tumors are C7, TNFRSF12A, MFGE8(up-regulated) and CXCL5, IFNL1, GZMH, HMGB1 and CXCR1 (down-regulated). Conclusions: There are significantly fewer cytotoxic and dendritic cells in late-stage MSI-H CRC, compared to early-stage MSI-H CRC, which is associated with decrease expression in JAK-STAT-IFN-γ- and antigen processing-related pathways. Citation Format: Kuo-Hsing Chen, Chia-Lang u Hs, Yu-Li Su, Chang-Tsu Yuan, Jia-Huei Tsai, Yi-Hsin Liang, Ann-Lii Cheng, Kun-Huei Yeh. The difference of immune microenvironment betweende novometastatic and non-metastatic microsatellite instability-high 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 5533.
Abstract 4535: JAB-26766: A small-molecule, orally bioavailable PARP7 inhibitor with high potency and selectivity
Authors: Di Kang, Yanping Wang, Xin Sun, Man Yan, Haijun Li, Mingming Chen, Yiwei Lin, Wei Long
Journal: Cancer Research (2024)

Abstract Background: PARP7 (also referred to as TIPARP or ARTD14) is a mono-ADP-ribosyl transferase that inhibits type I interferon (IFN) signaling. Targeting PARP7 to restore antitumor immunity represents a promising treatment strategy. We have developed JAB-26766, an orally bioavailable, highly potent, and selective PARP7 inhibitor. Methods: A time-resolved fluorescence energy transfer (TR-FRET) assay was applied to determine the binding and inhibition of PARP7 by JAB-26766. IFN-β secretion assay, STAT1 phosphorylation assay, and ISG (interferon stimulated gene) mRNA assay were performed to evaluate the inhibitory activities of JAB-26766 on the downstream signaling of PARP7. CellTiter-Glo assay was performed to evaluate cell viability upon treatment of JAB-26766. In vivo PK-PD study was conducted to evaluate the relationship between JAB-26766 concentration and the level of tumor STAT1 phosphorylation. The antitumor activity of JAB-26766 either as a single agent or in different drug combinations was evaluated in multiple mouse models. Results: High potency of JAB-26766 on PARP7 inhibition as well as &amp;gt;1800-fold selectivity over PARP2 was observed through biochemical assays. At the cellular level, JAB-26766 induced IFN-β secretion, up-regulated ISG mRNA levels, increased phosphorylation of STAT1, and inhibited cell viability of multiple tumor cell lines (with most IC50 values below 50 nM). JAB-26766 combined with a STING agonist resulted in synergistic activation of STING pathway, as evidenced by increased CXCL10 secretion, and inhibited tumor cell proliferation. In vivo PK-PD study showed that JAB-26766 exposure in plasma and tumor has good correlation with induction of tumor STAT1 phosphorylation. Furthermore, JAB-26766 showed potent antitumor activity and good tolerability either as monotherapy or combined with STING agonist or anti-PD-1 antibody in mouse models of non-small cell lung cancer, breast cancer and colorectal cancer. Conclusions: JAB-26766 is an orally bioavailable, highly potent, and selective PARP7 inhibitor that shows early promising anti-tumor activities. Citation Format: Di Kang, Yanping Wang, Xin Sun, Man Yan, Haijun Li, Mingming Chen, Yiwei Lin, Wei Long. JAB-26766: A small-molecule, orally bioavailable PARP7 inhibitor with high potency and selectivity [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 4535.
Abstract 5529: Mimicking CAFs, pial cells support leptomeningeal metastasis
Authors: Jenna Snyder, Jan Remsik, Adrienne Boire
Journal: Cancer Research (2024)

Abstract Leptomeningeal metastasis (LM), the spread of cancer into cerebrospinal fluid (CSF)-filled coverings of the brain and spinal cord, is a dismal complication of cancer leading to rapid neurologic disability and death. While a diverse array of primary tumors may result in LM, recent work from our laboratory (Chi Y et al 2020 Science) demonstrates a conserved transcriptional signature, independent of primary tumor, suggesting that tumor-microenvironmental interactions play a dominant role in this pathology. We have proteomically interrogated CSF collected from breast (n = 45), lung (n = 30), and melanoma (n = 27) patients with and without LM. We detect robust expression of inflammatory cytokines in all LM+ samples, 15 of these cytokines including IL8, IL6, and CXCL1 are conserved across tumor types in the presence of LM. Because cancer cells in the CSF do not express mRNA associated with these cytokines, we hypothesized that these inflammatory cytokines may originate from the microenvironment. Within the leptomeninges, LM cells adhere to and interact with the innermost layer of the meninges, the pia mater, which contains fibroblast-like cells. Co-culture of cancer cells with pial cells induced changes in the pial cell transcriptome and secretome, leading to increased IL8, IL6, and CXCL1 production. This communication between cancer cells and pial cells is preserved in the absence of direct cell-cell contact. These pial cells support cancer cell growth in vivo, as measured by co-implantation experiments. In addition, bulk RNA sequencing of mouse pial cells shows an inflammatory signature upregulated in the presence of LM. Taken together, these observations support a cancer-associated-fibroblast like role for pial cells in the setting of LM. Our work extends the CAF phenotype beyond classical fibroblasts to include pial cells, suggesting novel therapeutic opportunities within CNS malignancies. Citation Format: Jenna Snyder, Jan Remsik, Adrienne Boire. Mimicking CAFs, pial cells support leptomeningeal metastasis [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 5529.
Abstract 5578: Multi-omics approach reveals a SMAD4-deficiency signature, translational reprogramming and synthetic lethality in esophageal adenocarcinom
Authors: Julia V. Milne, Kenji Fujihara, Eric Kusnadi, Maree Pechlivanis, Niko Thio, Carlos Cabalag, Twishi Gulati, Jovana Gotovac, Kaylene Simpson, Cuong Duong, Luc Furic, Wayne Phillips, Nicholas Clemons
Journal: Cancer Research (2024)

Abstract Esophageal adenocarcinoma (EAC) is a cancer of high mutation burden with negligible recurrent and druggable driver genes and, therefore, a paucity of options for targeted therapy. Mutation or loss of the tumor suppressor gene SMAD4 occurs in up to 20% of EAC cases, and we have previously shown that loss of SMAD4 is sufficient to promote EAC tumorigenesis in an in vivo xenograft model. The present study aimed to delineate the role of SMAD4 in EAC tumorigenesis and identify synthetic lethal interactions in SMAD4-deficient cancers as a novel approach for treating EAC. Our multi-omics methodology integrated RNA-sequencing, proteomics, polysome-sequencing, reverse-phase protein arrays, and genome-wide CRISPR-Cas9 screening to unveil a SMAD4-deficiency signature and new therapeutic avenues for EAC. These data reveal a complex interplay between SMAD4 loss and regulation of mTOR signaling, with specific downstream effects to reprogram translation. SMAD4-deficient cells express decreased levels of 4E-BP1, the inhibitory binding partner of EIF4E, which is the rate-limiting component of the cap-dependent translation initiation complex. This was accompanied by increased mTOR activity, including phosphorylation and inactivation of 4E-BP1. We found that SMAD4-deficient cells exhibit vastly different polysome traces compared to their wildtype counterparts and preferentially upregulate cap-dependent translation, acquiring an addiction to translation of oncogenic mRNAs. Furthermore, perturbation of additional negative regulators of mTOR signaling in combination with SMAD4 knockout exacerbated these effects and accelerated tumorigenesis in vivo and growth of patient-derived organoids in vitro. This work advances our knowledge of EAC tumorigenesis, provides new mechanistic insights into SMAD4-driven transformation as well as novel potential therapeutic avenues for SMAD4-deficient EAC. Citation Format: Julia V. Milne, Kenji Fujihara, Eric Kusnadi, Maree Pechlivanis, Niko Thio, Carlos Cabalag, Twishi Gulati, Jovana Gotovac, Kaylene Simpson, Cuong Duong, Luc Furic, Wayne Phillips, Nicholas Clemons. Multi-omics approach reveals a SMAD4-deficiency signature, translational reprogramming and synthetic lethality in esophageal adenocarcinom [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 5578.
Abstract 5239: Discovery of AML associated therapeutic targets
Authors: Omar M. Ibrahim, Michael P. Rettig, Reyka G. Jayasinghe, Li Ding, John F. DiPersio
Journal: Cancer Research (2024)

Abstract Chimeric Antigen Receptor T-cell (CART) immunotherapy has shown significant success in the treatment of hematological malignancies. However, their efficacy in AML is limited due to the disease's genetic diversity and lack of uniform antigen targets. To identify potential AML cell-surface markers, we employed a comprehensive approach that involved the utilization of 3' single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (RNA-seq), and enhanced whole exome sequencing (eWES). A total of 21 samples were analyzed, comprising 18 distinct AML patients and 3 healthy bone marrow aspirates, serving as controls. We conducted scRNAseq on 21 samples, yielding a total of 185,106 high-quality cells, which were effectively clustered into 38 unbiased groups. Notably, tumor clusters exhibited highest copy number variations and formed separate clusters from other non-tumor immune cells. To uncover key functional pathways, we conducted pathway enrichment analysis comparing tumor cells to non-tumor cells. Our findings demonstrated a significant overrepresentation of cellular processes related to Allograft rejection, IL2/STAT5 signaling, IFN-gamma response and apoptosis. To identify AML specific markers, we performed an unbiased systematic search of the scRNAseq dataset for genes with unique expression patterns in tumor cells compared to the healthy bone marrow controls. Our analysis identified differentially expressed genes, with many genes displaying relative cell and tissue specificity. Notably, among these genes, we unveiled key potential targets with cell surface specificity, including novel markers alongside previously known ones. Noteworthy candidates, such as ADGRE2, CD33, CD123, CLEC12A, and FLT3 and understudied novel markers such as CD86, CSF1R, S100 proteins and VMP1, were prominently expressed, showcasing their potential significance as targets for engineered immunotherapy. To validate and consolidate our discoveries, we conducted a cross-referencing exercise by comparing our scRNAseq data against bulk RNA data from primary human AML samples and cell lines. Bulk global proteomics, flow cytometry-based and CART generation studies are ongoing to confirm our discoveries. Our rigorous computational and experimental approach provides valuable insights into tumor-specific cell surface proteins, which hold promise as potential targets for innovative and precision immunotherapeutic interventions in the realm of AML treatment. Citation Format: Omar M. Ibrahim, Michael P. Rettig, Reyka G. Jayasinghe, Li Ding, John F. DiPersio. Discovery of AML associated therapeutic targets [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 5239.
Abstract 676: The integrated stress activator BTM-3566 overcomes therapeutic resistance in mantle cell lymphoma
Authors: Yang Liu, Heng-Huan Lee, Joseph McIntosh, Yijing Li, Tianci Zhang, Wei Wang, Matthew J. Kostura, Michael Wang
Journal: Cancer Research (2024)

Abstract Successive generations of BTK inhibitors and CAR T-cell therapy have transformed the treatment of mantle cell lymphoma (MCL). However, treatment resistance has inevitably emerged, creating significant medical need. Recently a novel, clinical stage small molecule, BTM-3566, has been described that targets a mitochondrial process essential for Diffuse Large B-cell lymphoma (DLBCL) survival. BTM-3566 activates the mitochondrial protease OMA1, triggering the ATF4 integrated stress response (ISR). BTM-3566 has robust in vitro efficacy in DLBCL cell lines irrespective of genomic background and elicits complete tumor regression in multiple CDX and PDX mouse models of DLBCL. Based on the activity observed in DLBCL, we further explored the effectiveness of BTM-3566 in MCL models in vitro and in xenograft mouse models in vivo. BTM-3566 inhibited cell proliferation across a panel of MCL cell lines, irrespective of resistance status to ibrutinib and venetoclax (IC50s of 142.5-687.6 nM). Following a 24-hour treatment with BTM-3566, a dose-dependent increase in apoptosis was observed in four tested MCL cell lines—JeKo-1, JeKo-IBN-R, Mino, and Mino-VEN-R, as determined by increased caspase-3 activation and PARP cleavage. Similarly, western blot analysis revealed dose-dependent reductions in MCL-1 and c-MYC, accompanied by an increase in the transcription factor ATF4, indicative of activation of the stress response. We evaluated the in vivo efficacy of BTM-3566 in the JeKo-CDX mouse model. Daily oral administration of BTM-3566 at 10, 20 and 30 mg/kg (n = 5 for each group) in a 5-day on and 2-day off schedule resulted in tumor regression at all three doses (Treatment vs. Vehicle, p &amp;lt; 0.01). We expanded our investigation to PDX mouse models, including those derived from patients resistant to multiple therapies. Four PDX models encompassing naive, rituximab-resistant, BTKi-CAR T dual-resistant and BTKi-VEN-CAR T triple-resistant models were evaluated. BTM-3566 treatment results in nearly complete tumor growth inhibition associated with robust reductions in tumor burden in treated mice across all four PDX models (reduction in tumor weight at the study endpoint, p &amp;lt; 0.001). Notably, no toxicity was observed during the treatment period. In summary, BTM-3566 is effective in treating MCL in vitro and in vivo in preclinical studies. Citation Format: Yang Liu, Heng-Huan Lee, Joseph McIntosh, Yijing Li, Tianci Zhang, Wei Wang, Matthew J. Kostura, Michael Wang. The integrated stress activator BTM-3566 overcomes therapeutic resistance in mantle cell lymphoma [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 676.
Abstract 6029: 225Ac/89Zr labeled anti nectin 4 radioimmunoconjugates as theranostics against nectin 4 positive triple negative breast cancer
Authors: Hanan Babeker, Fabrice Njotu, Jessica Ketchmen, Florence Tikum, Alireza Doroudi, Emmanuel Nwangele, Maruti Uppalapati, Humphrey Fonge
Journal: Cancer Research (2024)

Abstract Nectin4 (N4) is a biomarker that is overexpressed in ~62% of triple negative breast cancer (TNBC) and its lack of expression in normal tissues makes it an ideal target for the therapy and PET imaging of TNBC. Methods: We developed a fully human antibody against nectin 4 (anti N4) using phage display. Anti N4 was radiolabeled with 89Zr &amp; 225Ac, respectively, for imaging &amp; radiotherapy using TNBC xenograft &amp; syngeneic mouse models. TNBC murine 4T1 cells were transduced with human N4 and N4 expression was confirmed by FACS. Biodistribution &amp; PET imaging of 89Zr anti N4 radioimmunoconjugate (RIC) was studied in mice bearing N4 positive xenografts. Dosimetry of 225Ac anti N4 was studied in healthy mice &amp; the therapeutic efficacy was evaluated for 90 days in mice bearing MDA MB 468 xenograft &amp; transduced 4T1 syngeneic models. Mice were treated with 2 doses of 350 nCi administered at 10 days apart. Tumor growth was monitored by a digital caliper. Results: The pharmacokinetic profile of 89Zr-anti-N4 RIC showed biphasic distribution with a moderate elimination of 63 h. PET imaging &amp; biodistribution of 89Zr anti N4 in mice bearing MDA MB 468 xenograft showed high tumor uptake of 13.2 ± 1.12 %IA/g at 120 h. 225Ac anti N4 was effectively internalized in MDA MB 468 and was cytotoxic to the cells with IC50 of 1.2 kBq/mL. Treatment with 225Ac anti N4 led to complete tumor remission in all mice bearing MDA MB 468 xenografts and 4T1 syngeneic model by day 20 and 28, respectively. Conclusions: 89Zr anti N4 was an effective PET imaging probe with specific uptake in tumor. 225Ac anti N4 was effective as a therapeutic agent resulting in complete remission of tumors in both mouse xenograft &amp; syngeneic models. These results are promising for the development of anti-N4 RICs as theranostics for TNBC. Citation Format: Hanan Babeker, Fabrice Njotu, Jessica Ketchmen, Florence Tikum, Alireza Doroudi, Emmanuel Nwangele, Maruti Uppalapati, Humphrey Fonge. 225Ac/89Zr labeled anti nectin 4 radioimmunoconjugates as theranostics against nectin 4 positive triple negative 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 6029.