tbuckley/cabot-search huggingface dataset:
Abstract A006: Loss of XIST induces tumor metabolism reprogramming in ovarian cancer
Authors: Ikrame Naciri, Minzhi Liang, Ying Yang, Maria De Lourdes Andrade Ludena, Heather Karner, Benjamin Lin, Alfredo Lebron, Mei Kong, Sha Sun
Journal: Cancer Research (2024)

Abstract Long noncoding RNAs (lncRNAs) have emerged as key players in various physiological processes, with dysregulation linked to diseases such as cancer. As diagnostic markers and therapeutic targets, lncRNAs have attracted considerable interest in cancer biology. XIST is one of the most studied lncRNAs, known as the master regulator of X chromosome inactivation (XCI) in mammals. The molecular mechanisms and regulatory elements of XCI have been extensively studied. However, their role in cancer susceptibility, particularly in female cancers, and their alterations in cancer cells remain elusive. To gain insight into the role of XIST in ovarian cancer, we analyzed TCGA ovarian cancer data and observed a downregulation of XIST expression in patients with high-grade ovarian cancer. In subsequent experiments, we performed CRISPR Cas9 inhibition (CRISPRi) to efficiently downregulate XIST expression in two ovarian cancer cell lines, OVCAR3 and SKOV3. Our functional and transcriptional analyses revealed a surprising finding: XIST downregulation did not result in widespread reactivation of X chromosome genes; however, we found an enrichment of gene related to oxidative phosphorylation pathway (OXPHO) in our cells with XIST knockdown. This finding was validated through measurement of the oxygen consumption rate, an indicator of OXPHO, which was higher in cells with downregulated XIST. In addition, we examined sequencing data from ovarian cancer patient samples and found that patients with low XIST expression showed an enrichment of genes related to oxidative phosphorylation, in accordance with our in vitro data. Under hypoxic stress, this metabolic shift resulted in increased colony formation and enhanced proliferation of ovarian cancer cells. Preliminary results from our xenograft experiments indicate enhanced tumor development with XIST-low cancer cells. Overall, our findings provide insight into the potential tumor suppressor role of XIST in ovarian cancer. Our study presents novel evidence implicating the XIST lncRNA in the metabolic oxidative phosphorylation pathway, thereby opening up the possibility of targeting this pathway for ovarian cancer patients with low XIST expression. Citation Format: Ikrame Naciri, Minzhi Liang, Ying Yang, Maria De Lourdes Andrade Ludena, Heather Karner, Benjamin Lin, Alfredo Lebron, Mei Kong, Sha Sun. Loss of XIST induces tumor metabolism reprogramming in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A006.
Abstract IA004: Targeting clonal heterogeneity in treatment-refractory Glioblastoma with novel and empiric immunotherapies
Authors: Sheila K Singh
Journal: Cancer Research (2024)

Abstract Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for the treatment of GBM. In this talk, we summarize recent clinical and pre-clinical efforts to develop immunotherapeutic and chimeric antigen receptor (CAR) T cell treatment strategies for GBM recurrence, including challenges in the form of fundamental mechanisms of therapy evasion by tumor cells, such as immense intratumoral heterogeneity, suppression of the tumor immune microenvironment, and low mutational burden. Insights from these advances and challenges have shaped our development of a translational research pipeline from initial target discovery, through target validation and exploration of mechanism, to building new biotherapeutics against novel cancer targets, and preclinical testing in our patient-derived animal models of treatment-resistant GBM. We have tracked GBM cell populations that undergo clonal evolution as a result of selective pressures exerted by standard treatments to identify the cellular composition of the recurrence, to allow us to determine the intracellular signaling pathways that drive GBM relapse. Ultimately, we will design rational combinations of therapeutics that can reignite the anti-tumor immune response, effectively and specifically target tumor cells, and reliably decrease tumor burden for GBM patients. Citation Format: Sheila K Singh. Targeting clonal heterogeneity in treatment-refractory Glioblastoma with novel and empiric immunotherapies [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr IA004.
Abstract PR-001: Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases
Authors: Selena Lorrey, Lucas Wachsmuth, Mackenzie Price, Corey Neff, Quinn Ostrom, Peter Fecci
Journal: Cancer Research (2024)

Abstract Immunotherapy is less effective against intracranial metastases compared to extracranial metastases and ineffective against primary brain tumors such as glioblastoma. Brain tumors present a unique challenge to in the context of immunotherapy, as these patients are immunosuppressed not just locally at the tumor, but also outside the CNS. Importantly, systemic immunosuppression observed in brain tumor patients limits the capacity of the immune system to respond to immunotherapy. Through this work we present a novel axis of immunosuppression in patients with intracranial tumors and demonstrate that overactive adrenergic signaling is a major barrier to immunotherapeutic success. Our data indicate that combining beta-adrenergic blockade with immunotherapy provides a survival benefit in the setting of brain tumors, where immunotherapy alone has proven ineffective. We demonstrate that this survival benefit is driven by a remodeling of the tumor microenvironment, increasing NF-kB activity and resulting in an increase in cDC1s and CD8+ T cells, as well as an increase in CD40-CD40L signaling, suggesting the immune system is poised to respond to immunotherapy. Further, we demonstrate that beta-adrenergic blockade can overcome systemic immunosuppression to restore the capacity of T cells to respond to an immune stimulus. Using the SEER-Medicaid database, we retrospectively examined outcomes in patients with melanoma and lung adenocarcinoma brain metastasis who received checkpoint blockade therapy alone vs those concurrently receiving beta-blocker therapy. We found that patients receiving combination therapy showed increased overall survival compared to those receiving checkpoint blockade alone. We then validated these findings in preclinical models of glioma, demonstrating that combining immunotherapy and propranolol, a widely prescribed FDA-approved beta-blocker, extended survival. Moving forward, we proffer that combination therapy with beta-blocker and immunotherapy, particularly checkpoint blockade, represents a promising translational treatment platform for patients with primary or metastatic intracranial malignancies. Citation Format: Selena Lorrey, Lucas Wachsmuth, Mackenzie Price, Corey Neff, Quinn Ostrom, Peter Fecci. Beta-adrenergic blockade licenses the use of immunotherapy in primary brain tumors and brain metastases [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-001.
Abstract A024: High throughput screen for identifying inducers of Autophagic Cell Death in Ovarian Carcinoma
Authors: Pahul Hanjra, Andrea Liu, Marc Ferrer, Anil K. Sood, Yunfei Wen
Journal: Cancer Research (2024)

Abstract Ovarian carcinoma continues to have the highest associated mortality among gynecologic malignancies. Despite surgery and chemotherapy, relapse and drug-resistant disease remains common. Thus, new therapeutic targets and improved combination regimens are needed. Autophagy is a conserved process cells use to remove and recycle old or damaged contents and maintain homeostasis, especially in times of cellular stress. Prolonged autophagy can result in cell death independently of apoptosis in a process known as autophagy cell death (ACD). This offers an alternative therapeutic strategy to target cancer cells, which are often resistant to apoptosis. In this study, we performed a high-throughput screen using the Mechanism Interrogation PlatE (MIPE) oncology library in HeyA8 and SKOV3 spheroids to identify drugs with high potential to induce ACD. Screening was performed in two phases: 1) Enrichment for compounds that decreased cell viability; 2) Enrichment for compounds able to induce autophagic flux in SKOV3 spheroids. We used a pft-LC3-RFP-GFP construct which was stably expressed in SKOV3 cells before 3-D culture as an autophagy index, and the accumulation of LC3-RFP in SKOV3 spheroids was measured in response to the treatments from MIPE compounds versus compared to control. An analog of the top hit of the screen results was the SIRT1 inhibitor, EX-527. We next performed a pharmacodynamic study in OVCA432-ip1-luc tumor-bearing mice to identify potential biomarkers of drug activity. We found that expression of the autophagy-related protein, LC3B, increased in tumors in a dose-dependent manner, forming loci indicative of autophagy flux at 20 mg/kg. Work is ongoing to identify rational combinations for use of EX-527 in management of ovarian carcinoma, and to characterize its mechanism of action. Citation Format: Pahul Hanjra, Andrea Liu, Marc Ferrer, Anil K. Sood, Yunfei Wen. High throughput screen for identifying inducers of Autophagic Cell Death in Ovarian Carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A024.
Abstract A005: Alanine metabolism is an ARID1A-dependent vulnerability in clear cell ovarian carcinoma
Authors: Hao Nie, Wei Zhou, Chen Wang, Nan Zhang, Shuai Wu, Rugang Zhang
Journal: Cancer Research (2024)

Abstract ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ~50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the alanine transporter SLC38A2 synergizes with immune checkpoint blockade (ICB) in ARID1A-inactivated OCCCs. Unbiased metabolic profiling revealed that alanine levels were increased by ARID1A inactivation in OCCC cells. In addition, using genome-wide approaches, we discovered that SWI/SNF inactivation downregulates SLC7A8 that is responsive for alanine secretion, while upregulating SLC38A2 that uptakes alanine extracellularly. This creates a dependence on the alanine consumption in ARID1A-inactivated cells. Inhibition of SLC38A2 reduces alanine uptake, impairs mitochondrial respiration, and induces cell cycle arrest and ARID1A inactivation exacerbates these effects. SLC38A2 inhibition suppresses the growth of ARID1A mutant, but not wildtype, OCCCs. In addition, SLC38A2 inhibition synergizes with anti-PD-L1 antibody in a genetic OCCC mouse model driven by conditional ARID1A inactivation. Our data indicate that inhibition of the alanine metabolism simultaneously suppresses tumor cell growth and boosts antitumor immunity, which synergizes with immune checkpoint blockade in suppressing ARID1A-mutated cancers. Citation Format: Hao Nie, Wei Zhou, Chen Wang, Nan Zhang, Shuai Wu, Rugang Zhang. Alanine metabolism is an ARID1A-dependent vulnerability in clear cell ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A005.
Abstract B022: Interplay between the cellular dntp pool and dna double-strand break repair: a potential therapeutic target for refractory glioblastoma
Authors: Dominique Monroe, Edidiong Usoro, Arilyn Williams, Shelby Aycox, Emily Steinbeck, Waaqo Daddacha
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is a deadly brain tumor resistant to double-strand break (DSB)-inducing therapeutics due to dysregulated DNA-repair. Ionizing radiation (IR) and some chemotherapeutics strategically target cancer cells by causing DNA-DSBs, resulting in cell death if left insufficiently repaired. Homologous Recombination (HR) is an error-free DSB-repair process consisting of proteins that are often dysregulated in GBM, causing overactive DNA-repair, therapy resistance, and poor patient outcomes. Proteins involved in the HR-repair process have been extensively investigated; however, therapeutic resistance remains common. Here, we provide an alternative approach to target DSB-resistant GBM by modulating the dNTP pool instead of only targeting DNA-repair proteins. Our goal is to understand the interplay between dNTP pools and DSB-repair. dNTPs are a necessary constituent to repair DSBs; however, the role of the dNTP pool in DNA damage repair is not fully understood. Previous research shows that the dNTP pool remains unchanged after inducing DSBs, highlighting the importance of a tightly regulated dNTP pool. Our results show that increasing the dNTP pool significantly increased apoptosis and reduced cancer cell viability after IR. We found that a higher cellular dNTP pool impaired HR-mediated DSB-repair by delaying DNA end-resection in HR. Filling this gap in our knowledge may provide new avenues to sensitize therapy-resistant cancers, enhancing the efficacy of DSB-inducing therapies. Citation Format: Dominique Monroe, Edidiong Usoro, Arilyn Williams, Shelby Aycox, Emily Steinbeck, Waaqo Daddacha. Interplay between the cellular dntp pool and dna double-strand break repair: a potential therapeutic target for refractory glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B022.
Abstract B051: DNA damage signaling activates GTP synthesis to promote glioblastoma treatment resistance
Authors: Andrew J. Scott, Alexandra O'Brien, Weihua Zhou, Jie Xu, Sravya Palavalasa, Ayesha U. Kothari, Kari Wilder-Romans, Li Zhang, Anthony C. Andren, Sriram Chandrasekaran, Jason Heth, Yoshie Umemura, Nathan Qi, Theodore S. Lawrence, Wajd N. Al-Holou, Costas A. Lyssiotis, Daniel R Wahl
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is the most common type of invasive brain tumor in adults and is uniformly fatal due to inherent resistance to radiation therapy (RT) and chemotherapy. Our group and others have found that metabolites can regulate DNA repair and therapy resistance in brain tumors, but little is known about how DNA damage regulates metabolic pathway activity in cancer. Here we show that following treatment with RT, GBMs increase rates of de novo guanylate synthesis in vitro and in orthotopic patient-derived xenograft models via signaling through the DNA repair protein DNA-PK. To determine if disrupting this regulation can augment GBM treatment efficacy, we combined an FDA-approved inhibitor of purine synthesis (mycophenolate mofetil, MMF) with chemoradiation in a variety of mouse models of GBM. Critically, targeting GTP synthesis improved the efficacy of both RT alone and chemoradiation in multiple patient-derived and syngeneic intracranial models. Our translational studies have shown that mycophenolic acid, the active metabolite of MMF, penetrates the blood-brain barrier at concentrations sufficient to inhibit GTP synthesis in GBMs of human patients. The phase 1 arms of our study, which are ongoing, are testing the safety and efficacy of combining MMF with standard of care chemoradiation for patients with primary and recurrent GBM. Citation Format: Andrew J. Scott, Alexandra O'Brien, Weihua Zhou, Jie Xu, Sravya Palavalasa, Ayesha U. Kothari, Kari Wilder-Romans, Li Zhang, Anthony C. Andren, Sriram Chandrasekaran, Jason Heth, Yoshie Umemura, Nathan Qi, Theodore S. Lawrence, Wajd N. Al-Holou, Costas A. Lyssiotis, Daniel R Wahl. DNA damage signaling activates GTP synthesis to promote glioblastoma treatment resistance [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B051.
Abstract PR-010: Asc1lb progenitor-specific RB conditional inactivation in zebrafish models rare CNS primitive neuroectodermal tumors
Authors: Maura McGrail, Fang Liu, Sekhar Kambakam, Zhitao Ming
Journal: Cancer Research (2024)

Abstract We generated a new zebrafish model of human brain cancer by Cre/lox regulated conditional inactivation of the tumor suppressor RB in embryonic neural progenitors. An ascl1b progenitor Cre driver was used to inactivate RB by Cre recombination of an intronic floxed mRFP gene trap cassette, leading to mRFP expression and lineage labeling of RB mutated cells. Beginning at 6 months of age adult fish developed poorly differentiated brain tumors, similar to our previous zebrafish brain tumor model generated by CRISPR targeting of RB in embryos. Tumor transcriptome analysis revealed a proneural transcription factor molecular signature of the olig2+/sox10+ human CNS primitive neuroectodermal tumor subtype. Overexpression of chromatin remodelers suggest epigenetic mechanisms may contribute to tumorigenesis. Our model will allow sorting of RB mutant cells from the earliest stage of mutagenesis in the embryo to induction of cellular transformation in juveniles. With this approach we can profile the epigenetic time course of cellular transformation and reveal new insight into the molecular mechanisms driving PNET oncogenesis. Our approach to model cancer in fish with Cre/lox conditional inactivation can be applied to other cell lineages and brain tumor types. Citation Format: Maura McGrail, Fang Liu, Sekhar Kambakam, Zhitao Ming. Asc1lb progenitor-specific RB conditional inactivation in zebrafish models rare CNS primitive neuroectodermal tumors [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr PR-010.
Abstract A058: Mesenchymal stem cells act as a selective pressure for High Grade Serous Ovarian Cancer initiation
Authors: Geyon L. Garcia, Huda I. Atiya, Lan G. Coffman
Journal: Cancer Research (2024)

Abstract High grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer accounting for 80-90% of diagnoses. Despite its high incidence and mortality, the mechanisms of cancer initiation are unclear. The majority of HGSOC originates in the fallopian tube epithelium (FTE) with support of underlying mesenchymal stromal/stem cells (MSCs). MSCs are stromal progenitor cells that play important roles in wound healing and, in the context of cancer, tumor progression. We showed that MSCs within the tumor microenvironment, termed cancer associated MSCs (CA-MSCs) harbor a unique, age-associated epigenetic signature that is essential for tumor growth and metastasis. Surprisingly, we identified rare subsets of MSCs from benign tubes that exhibit similar epigenetic changes to cancer educated CA-MSCs suggesting that the pro-oncogenic MSC phenotype exists prior to cancer initiation. These “high risk” MSCs (hrMSCs) increase with age, are enriched in BRCA mutation carrier patients, promote cancer cell proliferation, and most notably, elicit tumor formation in primary, non-cancerous FTE. To elucidate the mechanism of hrMSC-induced malignant transformation of FTE, we characterized the effect that hrMSCs have on primary FTE. HrMSCs promoted increased growth of FTE relative to normal/low risk MSCs (lrMSCs) derived from the same patient. These MSCs lack the epigenetic signature/transcriptome of hrMSCs/CA-MSCs. Intriguingly, we co-cultured FTE with hrMSCs at a 1:1 ratio and discovered robust DNA damage in the form of DNA double strand breaks (53BP1 foci) in FTE at 24 hours. Furthermore, conditioned media from hrMSCs supported the recovery of FTE following damage with other DNA damaging agents. We hypothesize that the DNA damage function of hrMSCs serves as a selective pressure for mutation in FTE (1st hit). Additionally, we hypothesize that hrMSCs simultaneously provide growth signals to FTE allowing for evasion of DNA damage-induced cell death (2nd hit). Lastly, we hypothesize that both hrMSC functions are required for genesis of HGSOC. Citation Format: Geyon L. Garcia, Huda I. Atiya, Lan G. Coffman. Mesenchymal stem cells act as a selective pressure for High Grade Serous Ovarian Cancer initiation [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A058.
Abstract A026: Identifying mechanisms to target in combination with trametinib to improve therapeutic efficacy in low-grade serous ovarian cancer
Authors: Rebekah M. Peplinski, Silvana Pedra Nobre, Jacob L. Schillo, Keely K. Ulmer, Yasmin A. Lyons, Jesse D. Riordan, Michael J. Goodheart, Adam J. Dupuy
Journal: Cancer Research (2024)

Abstract Low-grade serous ovarian cancer (LGSOC) has recently been characterized as a unique subtype of ovarian cancer with distinct molecular characteristics, clinical treatments, and therapeutic responses. Although LGSOC accounts for ~5% of ovarian cancers, the age of onset is younger (~45 years) than other subtypes and has a low response rate (~4%) to the standard of care chemotherapy. One defining characteristic of LGSOC is frequent genetic alterations in the MAPK pathway, which has led to recent MAPK-targeted therapeutic clinical trials. MEK inhibition, particularly with trametinib, has been shown to be effective in patients with recurrent LGSOC (Phase II/III Trial: GOG 281/LOGS). However, these patients eventually develop therapeutic resistance and progressive disease, with no remaining treatment options. Here we sought to characterize the biology of LGSOC and its response to trametinib in an effort to identify candidate mechanisms that may be targeted in combination with trametinib to improve therapeutic efficacy and outcomes for LGSOC patients. After characterizing trametinib responses and identifying cytotoxic doses for a panel of LGSOC cell lines (ES2, OVCAR8, VOA7681, OV7, and OV56), we performed RNA sequencing on each cell line under basal conditions, as well as after 24-hour or 7-day exposure to an IC95 dose of trametinib. These experiments identified both acute and longer-term transcriptional changes that occur in response to trametinib. CRISPR screens targeting the kinome were also performed to identify synthetic lethal interactions between trametinib treatment and loss of function of specific protein kinases. Integrated analysis of these approaches identified several potential candidates (AKT, mTOR, CDKs, among others) that may be targeted in combination with trametinib to improve LGSOC patient outcomes. Experiments testing synergistic relationships between trametinib and other FDA approved inhibitors were performed. Using these combination therapeutic approaches could re-sensitize cells to trametinib treatment or prevent the emergence of resistance, thereby improving therapeutic efficacy. If successful, a similar approach could be used in a clinical trial to treat patients with LGSOC. Citation Format: Rebekah M. Peplinski, Silvana Pedra Nobre, Jacob L. Schillo, Keely K. Ulmer, Yasmin A. Lyons, Jesse D. Riordan, Michael J. Goodheart, Adam J. Dupuy. Identifying mechanisms to target in combination with trametinib to improve therapeutic efficacy in low-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A026.