tbuckley/cabot-search huggingface dataset:
Abstract 4657: Investigating the role of circulating bone cells in melanoma patients on immune checkpoint inhibitor therapy
Authors: Nicholas Rozza, Catalin Mihalcioiu, Richard Kremer
Journal: Cancer Research (2025)

Abstract Bone metastasis is a frequent progression of metastatic melanoma affecting 20-40% of patients with metastatic melanoma. While immune checkpoint inhibitors have been revolutionary in the treatment of advanced melanoma, certain patient populations do not respond to immunotherapy. Clinical data from our own treated melanoma population at the MUHC has shown that patients with bone metastases respond poorly to immune checkpoint inhibitors and have worse outcomes when compared to patients without bone metastases. These findings have prompted the investigation into this observed phenomenon of treatment resistance. The bone microenvironment is known to be a key player in cancer progression and metastasis and has been shown to form a vicious cycle where cancer and bone cells interact symbiotically to promote tumor growth and enhance bone degradation. Bone cells that are released into the circulation during the dynamic process of bone metastasis can easily interact with immune cells and may disrupt the ability of the immune system to mount an effective anti-cancer response. In our cohort of 185 metastatic melanoma patients treated with immune checkpoint inhibitors, patients with bone metastasis have a 43% response rate versus 65% in patients with visceral metastases alone. In terms of the complete response (CR) rate, only 18% of patients with bone metastasis achieved a complete response compared to 52% of patients with visceral metastasis alone. The treatment resistance appears to be systemic in patients with bone metastasis; the response rate in lesions outside the bone is also reduced. In a subset of these patients with serial prospective blood collections, we profiled PBMCs to identify certain immune and bone cell populations in the circulation at a pre-treatment baseline, early on treatment 2-3 cycles and after 4-6 cycles depending on the regimen. Patients were grouped based on objective response to determine the relationship between clinical outcome and immune/bone cell profiles. Patients with bone metastasis and a poor response had reduced immune effector cells and increased osteocalcin positive bone cells in the circulation when compared to patients that achieved partial and complete responses. Immune and bone cell profiling is a novel method of evaluating melanoma patients undergoing immunotherapy and may serve as an effective predictor of response to immune checkpoint inhibitors. Citation Format: Nicholas Rozza, Catalin Mihalcioiu, Richard Kremer. Investigating the role of circulating bone cells in melanoma patients on immune checkpoint inhibitor therapy [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 4657.
Abstract 2514: Refining oncology dose selection: A framework for tailored dose optimization in the era of targeted and immunotherapies
Authors: Neekesh Dharia, Jiawen Zhu, Amy Schroeder, Sabine Frank, Christophe Boetsch, Candice Jamois, Nastya Kassir, Koorosh Korfi, Elizabeth Punnoose, Anjali Vaze, Peter Trask, Pritti Gosai, Jane Fridlyand, Chunze Li
Journal: Cancer Research (2025)

Abstract Historically, oncology dose selection was driven by the identification of the maximum tolerated dose, often resulting in significant toxicity. The advent of molecular targeted therapies and immunotherapies has created opportunities to achieve similar efficacy at a lower, more tolerable dose. Recent FDA draft guidance highlights the importance of dose optimization in drug development. Building on this, we present a novel framework categorizing drugs into four molecular classes based on their mechanisms of action: (1) small molecule targeted therapies and antibody-drug conjugates, (2) large molecule antagonists, (3) cancer immunotherapy agonists, and (4) molecules with limited or no single-agent activity. Unique considerations and strategies for dose optimization are detailed for each class, supported by case examples. We propose integrating proof of activity as a gating criterion for dose expansion to inform robust dose decisions and maximize the use of patient resources. This perspective underscores the integration of preclinical and clinical data—including pharmacokinetics, pharmacodynamics, and patient-reported outcomes—combined with quantitative pharmacology and statistical modeling, to optimize doses effectively while balancing efficacy and safety. While no one-size-fits-all approach exists, this tailored guidance for specific mechanistic classes provides balanced approaches to dose optimization that ultimately enhance the probability of success in drug development. Citation Format: Neekesh Dharia, Jiawen Zhu, Amy Schroeder, Sabine Frank, Christophe Boetsch, Candice Jamois, Nastya Kassir, Koorosh Korfi, Elizabeth Punnoose, Anjali Vaze, Peter Trask, Pritti Gosai, Jane Fridlyand, Chunze Li. Refining oncology dose selection: A framework for tailored dose optimization in the era of targeted and immunotherapies [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 2514.
Abstract 4966: Understanding social capital and health care treatment delays for cervical cancer survivors: a cross-sectional study using All of Us data
Authors: Samantha Garcia, Angel Arizpe, Albert J. Farias, Brittany N. Morey, Brenda Y. Hernandez, Lawrence A. Palinkas, Lourdes Baezconde-Garbanati, Jennifer Tsui
Journal: Cancer Research (2025)

Abstract Black and Latina women are more likely to report heath care delays when receiving treatment for cervical cancer compared to other racial and ethnic groups. Although studies have found higher social capital to be associated with higher cervical cancer screening, it is unclear if social capital is associated with health care delays among women diagnosed with cervical cancer. The purpose of this study was to examine the role of social capital (resources rooted in social networks) on treatment delays in a national sample of cervical cancer survivors from the All of Us dataset. We assessed the relationship between neighborhood social capital and healthcare delays (i.e., experienced at least one health care delay) among women self-reporting they have ever been diagnosed with cervical cancer. We conducted multivariable logistic regression to assess the association between social capital and health care delays while accounting for potential confounding variables (i.e., socioeconomic status, race, marital status, nativity status). Approximately 20% of participants (N=1,009) encountered health care treatment delays. Higher social capital was associated with lower odds of experiencing a health care treatment delay among women diagnosed with cervical cancer after adjusting for confounders (OR = 0.67, CI: 0.60, 0.79). Compared to their White counterparts, Black (OR = .63, CI: 0.50, 0.80) and Hispanic (OR = 0.74, CI: 0.60, 0.90) women had lower levels of self-reported social capital. Social capital was unrelated to nativity status among sample participants. Findings suggest that the development of social capital may help to reduce health care treatment delays among racially and ethnically diverse communities. Understanding how healthcare delays impact cancer care follow-up is an important step towards addressing cancer equity. Citation Format: Samantha Garcia, Angel Arizpe, Albert J. Farias, Brittany N. Morey, Brenda Y. Hernandez, Lawrence A. Palinkas, Lourdes Baezconde-Garbanati, Jennifer Tsui. Understanding social capital and health care treatment delays for cervical cancer survivors: a cross-sectional study using All of Us data [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 4966.
Abstract 4421: Chemotherapy-induced DNA damage triggers caspase-dependent degradation of N6-methyladenosine reader YTHDF proteins, reshaping the cancer transcriptome
Authors: Sang Eun Lee, Sung-Yup Cho
Journal: Cancer Research (2025)

Abstract N6-methyladenosine (m6A) modification plays a crucial role in DNA damage response (DDR), which is the primary mechanism targeted by most chemotherapeutic agents. Here, we investigated the dynamic regulation of m6A-related molecules during chemotherapy-induced DNA damage. Anthracycline treatment led to a significant reduction in protein levels, but not mRNA levels, of m6A readers YTHDF1, YTHDF2, and YTHDF3. It was consistently observed with other chemotherapeutic agents, including 5-fluorouracil (5-FU) and oxaliplatin. Notably, this reduction occurred independently of p53 status, as YTHDF proteins remained unchanged upon p53 overexpression alone, while their reduction was still observed in p53-knockout cells treated with doxorubicin. Mechanistic studies showed that the decrease in YTHDF proteins was primarily associated with topoisomerase II inhibition rather than reactive oxygen species (ROS) generation, which are both known mechanisms of doxorubicin. Further investigation revealed decreased protein stability of YTHDFs upon doxorubicin treatment, which was primarily attributed to activated caspase-mediated degradation during apoptosis rather than proteasomal degradation or autophagy. RNA sequencing analysis of YTHDF2-overexpressing cells showed differential enrichment of MYC targets V1, V2 pathway upon doxorubicin treatment, indicating a potential role for YTHDF2 in modulating oncogenic pathways during chemotherapy response. Collectively, our findings unveil mechanisms of m6A reader regulation during chemotherapy and suggest potential therapeutic implications for cancer treatment through manipulation of m6A-mediated gene regulation. Citation Format: Sang Eun Lee, Sung-Yup Cho. Chemotherapy-induced DNA damage triggers caspase-dependent degradation of N6-methyladenosine reader YTHDF proteins, reshaping the cancer transcriptome [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 4421.
Abstract 7250: Extracellular acidity in the TME interferes with the IFN-γ induction of the immunoproteasome
Authors: Matthew G. Smith, Alexis Ramos, Heena Panchal, Adam Mailloux
Journal: Cancer Research (2025)

Abstract The immunoproteasome (IP) is a component of the MHC class I presentation pathway (MHC1PP) that is induced by IFN-γ, functions to augment the immunogenicity of cancer cells by generating optimal tumor antigens from polypeptide precursors, and is correlated with favorable responses to immunotherapy. Understanding tumor intrinsic factors that regulate the IP in cancer is essential for addressing immunologically cold tumors which respond poorly to immunotherapy. Extracellular acidity (pH 6.5) is a hallmark of solid tumors and despite being shown to impair CD8+ anti-tumor immunity, remains understudied as a driver of immune-evasion in cancer. Here, we present data that extracellular acidity in vitro can restrict the induction of the catalytically active subunits of the IP, in particular 20s proteasome subunit beta type 9 (β1i) and 20s proteasome subunit beta type 10 (β2i). Various human and murine cancer cell lines (Human: pancreatic ductal adenocarcinoma PANC1, hepatocellular carcinoma HEPG2, non small cell carcinoma A549; Murine: non small cell carcinoma LLC) were cultured in control media (DMEM pH 7.4) versus acidic media (DMEM pH 6.5) and stimulated with IFN-γ to induce the IP. Cell lysates were assessed by Western blot and demonstrated a sharp reduction in the protein induction of β1i and β2i, which are both required for the formation of the mature IP, under acidic conditions compared to controls. RT-PCR analysis of A549 cells indicates that these proteins are blocked transcriptionally as well as translationally. Mechanistically, we demonstrate via Western blot that activation of signal transducer and activator of transcription 1 (STAT1), the critical transcription factor required for IFN-γ induction of the IP, is delayed in acidic conditions compared to controls. We further show that signal transducer and activator of transcription 3 (STAT3), a pro-tumorigenic transcription factor and antagonist of STAT1 transcriptional activity, is activated under acidic conditions in A549 cells and furthermore IFN-γ enhances this STAT3 activation but only under acidic conditions. Functionally, we show via flow cytometry that downstream of the blockade in IP subunit induction that occurs under acidic conditions, surface MHC I expression is diminished. Overall, these studies indicate extracellular acidity in the TME restricts the induction of IP components potentially through a STAT3 dependent mechanism, suggesting that targeting STAT3 activation in acidic tumors may improve tumor immunogenicity and responses to immunotherapy. Citation Format: Matthew G. Smith, Alexis Ramos, Heena Panchal, Adam Mailloux. Extracellular acidity in the TME interferes with the IFN-γ induction of the immunoproteasome [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 7250.
Abstract 233: Targeting Rho GTPases RAC1 and CDC42 in advanced prostate cancer cells
Authors: Wilfred Fonseca Ferrer, Valeria Torres Matos, Carolina Restrepo Soto, Jessica Colon Gonzalez, Suranganie Dharmawardhane Flanagan, Cornelis P. Vlaar Stoop, Carlos Joel Diaz Osterman
Journal: Cancer Research (2025)

Abstract BACKGROUND: The androgen receptor (AR) plays a central role in the development and progression of prostate cancer. Standard treatment for advanced prostate cancer targets the AR using androgen deprivation therapy. Despite initial responses, patients eventually progress to androgen-independent disease with metastasis, raising the need for novel treatment options. GTPases regulate many metastasis-associated processes, including cell division, cell growth, cell migration, and cell adhesion. Novel inhibitors for GTPases are currently being evaluated for efficacy in metastatic breast cancer. However, little is known about their utility for other hormone-dependent cancers such as prostate cancer. We hypothesize that Rho GTPase inhibitor efficacy will vary between prostate cancer cell models based on AR expression status and metastatic potential. This study aims to determine the efficacy of nine compounds targeting the GTPase pathway in the setting of AR-positive compared to AR-negative prostate cancer cells. METHODS: AR-positive (LNCaP, 22rv1) and AR-negative (PC3, DU145) prostate cancer cell lines were used to evaluate the efficacy of nine novel Rho GTPase inhibitors. MTT viability assays were performed following exposure of cells to 0-100μM compound for 72 hours. Migration assays were performed using sublethal doses of select compounds for 3-5 days. Intracellular expression of Rho GTPase-associated proteins was evaluated using Western blot. RESULTS: Of the compounds analyzed, six had an IC50 in the nanomolar range. The most effective compound overall was CPV-337 (IC50: 6.5-108.6nM). AR-negative cell lines exhibited a higher sensitivity to EHOP-097 and MBQ-168 than AR-positive cell lines. Proteins associated with mechanotransduction were elevated in AR-negative compared to AR-positive cells. CONCLUSION: Our study demonstrates a central role for Rho GTPases in prostate cancer metastatic potential in the context of AR independence. ACKNOWLEDGEMENTS: These studies were supported by start-up funds provided to C.J.D.O. by the University of Puerto Rico Comprehensive Cancer Center in San Juan, Puerto Rico. Citation Format: Wilfred Fonseca Ferrer, Valeria Torres Matos, Carolina Restrepo Soto, Jessica Colon Gonzalez, Suranganie Dharmawardhane Flanagan, Cornelis P. Vlaar Stoop, Carlos Joel Diaz Osterman. Targeting Rho GTPases RAC1 and CDC42 in advanced prostate cancer cells [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 233.
Abstract 4210: Replication stress detection using STRIDE technology platform
Authors: Karolina Stępień, Kamila Schirmeisen, Jakub Lechowski, Magdalena Bartyńska, Magdalena Kordon-Kiszala, Kamil Solarczyk
Journal: Cancer Research (2025)

Abstract Replication stress, characterized by the slowing or stalling of replication forks, is a hallmark of many cancers and a key driver of genomic instability. Therapeutics targeting the ATR kinase, a central regulator of the replication stress response, have emerged as promising strategies for selectively exploiting the vulnerabilities of cancer cells. A reliable marker of replication stress is essential to better understand its dynamics and to optimize the development and application of DNA damage response (DDR) inhibitors. Such markers can provide critical insights into therapeutic mechanisms and enhance the precision of targeted treatments. Single-strand DNA breaks (SSBs) are both a cause and a consequence of replication stress, making them a potential biomarker. However, their occurrence during normal metabolism requires additional specificity, which can be provided by detecting replication stress-associated proteins. Here, utilizing our STRIDE technology platform, we combined direct in situ detection of SSBs with protein markers leading to the development of an assay aimed at measuring replication stress levels. The assay combined the detection of single-strand DNA breaks (SSBs) with replication stress-associated proteins: RPA, RAD17, and RAD9, evaluated separately in distinct assay variants. Each variant was assessed for steady-state readouts, negative control signal levels, and sensitivity to replication stress induced by known compounds. All variants effectively informed on replication stress induction, and baseline readouts of the assays correlated with the cellular response to replication stress-inducing agents. Importantly, the assays were also tested on FFPE tissue sections, demonstrating their feasibility for application to this type of material. The data collected thus far suggests that all assay variants hold potential as effective replication stress markers. Additional studies are required to further refine these assays, determine their optimal use in different contexts, and confirm their utility in identifying high replication stress backgrounds to predict responses to drugs targeting proteins involved in the replication stress response. Citation Format: Karolina Stępień, Kamila Schirmeisen, Jakub Lechowski, Magdalena Bartyńska, Magdalena Kordon-Kiszala, Kamil Solarczyk. Replication stress detection using STRIDE technology platform [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 4210.
Abstract 5389: Adaptive OXPHOS and antioxidant defense in glucose-deprivation-resistant colon cancer cells
Authors: Elimelech Nesher, Subha Ranjan Das, Bar Levi, Igor Koman
Journal: Cancer Research (2025)

Abstract Cancer cells are generally characterized by exhibiting the Warburg effect, favoring glycolysis over oxidative phosphorylation (OXPHOS) to produce ATP. This leads to an increase in glucose uptake and lactate production, fueling rapid proliferation by providing energy and intermediates for biosynthesis. In parallel, slow angiogenesis resulting in a blood supply insufficient for the tumor's rapid growth leads to glucose starvation in solid tumors. To mimic glucose starvation in vitro, we used a model of glucose deprivation in HCT116 cells. A Seahorse study demonstrated that HCT116 cells endured an adaptive state of dormancy during glucose deprivation, shifting their metabolic pathway from glycolysis to OXPHOS. Interestingly, a small percentage of survived cells after dormancy completely resumed their proliferative abilities without glucose supply. We showed that these glucose-deprivation-resistant (GDR) cells have significant activation in the tricarboxylic acid (TCA) cycle, as well as increased levels of antioxidants and their precursors, such as GSSG, GSH, glutamine, glutamate, proline, betaine, citrulline, and arginine. These findings suggest that GDR cells could scavenge reactive oxygen species (ROS) generated during accelerated OXPHOS. Furthermore, the GDR cells demonstrated additional resistance to oxidative stress, induced by hydrogen peroxide. Increased OXPHOS in dormant cells, associated with elevated ROS production, led to significant DNA damage. In turn, enhancing DNA repair mechanisms and boosting antioxidant activity in GDR cells were accompanied with one-carbon metabolism, supporting rapid proliferation by supplying nucleotides for DNA repair and synthesis. We believe that cancer cells which, under glucose starvation, can completely switch their metabolism from glycolysis to OXPHOS are able to survive and regain their proliferative capacity by boosting their antioxidant defenses and improving their DNA repair mechanisms. This phenomenon supports the thesis that targeting cancer cells' metabolic flexibility and antioxidant capacity is an effective anticancer therapeutic strategy. Citation Format: Elimelech Nesher, Subha Ranjan Das, Bar Levi, Igor Koman. Adaptive OXPHOS and antioxidant defense in glucose-deprivation-resistant colon cancer cells [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 5389.
Abstract 5396: NDUFA4L2 inhibits oxidative phosphorylation to drive primary tumor escape
Authors: Emily Nicole Arner, Erin Q. Jennings, Daniel Crooks, Christopher J. Ricketts, Matthew A. Cottam, Kimryn Rathmell, Jeffrey C. Rathmell
Journal: Cancer Research (2025)

Metastasis causes most cancer deaths and cancer cells require metabolic adaptation to spread to new tissues. However, the metabolic requirements of epithelial to mesenchymal transition (EMT) for primary tumor escape are uncertain. Analyses of Renal Cell Carcinoma (RCC) tumors found mesenchymal cancer cells had elevated expression of the mitochondrial electron transport inhibitor NDUFA4L2 and were glycolytic. NDUFA4L2 suppressed oxidative phosphorylation and was essential for EMT and spontaneous metastasis in RCC models. Mechanistically, NDUFA4L2 caused a build-up of TCA cycle intermediates and modified chromatin accessibility of EMT-related loci. This appeared due to altered mitochondrial oxidative phosphorylation, as increased electron transport complex 1 inhibited EMT and Fumarate Hydratase deficiency drove metastasis. Impaired oxidative phosphorylation thus drives EMT, which is essential for primary tumor escape and metastasis. Citation Format: Emily Nicole Arner, Erin Q. Jennings, Daniel Crooks, Christopher J. Ricketts, Matthew A. Cottam, Kimryn Rathmell, Jeffrey C. Rathmell. NDUFA4L2 inhibits oxidative phosphorylation to drive primary tumor escape [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 5396.