tbuckley/cabot-search huggingface dataset:
Development of AB-2100, an autologous integrated circuit T (ICT) cell therapy targeting CA9 intended for the treatment of ccRCC.
Authors: Mark Landon, Irene Scarfo, Marvin Chew, Rakesh Sudhakah, Michelle Nguyen, Suchismita Mohanty, Jeremy Chen, Alma Gomez, Nickolas Attanasio, Amanda Fearon, Ivan Chan, Vibhavari Sail, Thomas Gardner, Beatriz Millare, Vince Thomas, Stanley Zhou, Jenessa Smith, Jennifer Mcdevitt, Angela Boroughs, Levi Gray-Rupp
Journal: Journal of Clinical Oncology (2024)

472 Background: Relapsed/refractory clear cell renal cell carcinoma (ccRCC) progressing after treatment with CPI and VEGF inhibitor remains an area of unmet need. We have developed AB-2100, an autologous, integrated circuit T (ICT) cell engineered to include three new features: a sequential “AND” logic gate that requires the IO presence of two antigens in the tumor microenvironment (TME) to trigger T cell killing; a shRNA-miR module to enhance resistance to suppressive TME via constitutive knockdown of FAS and TGFBR2; and a constitutive synthetic pathway activator (SPA) that increases STAT3 signaling for enhanced T cell cytotoxicity and expansion. Methods: A previous clinical study of CA9-specific CAR-T cell therapy was limited by on-target, off-tumor toxicity. To overcome this, AB-2100 includes a sequential “AND” logic gate that consists of a priming receptor (PrimeR) targeting PSMA, and a CA9-targeted CAR that is upregulated upon PrimeR engagement with PSMA expressed on the tumor neovasculature. A series of assays were performed to assess the specificity and potency of AB-2100: dual-antigen specificity of the logic gate was assessed in vitro and in vivo against CA9+ and PSMA+CA9+ tumors; vascular priming was modeled by co-culturing AB-2100 cells with PSMA-expressing endothelial cells and CA9+ tumor cells; a FAS cross-linking assay was conducted to assess the impact of FAS knockdown; the enhanced anti-tumor activity conferred by TGFBR2 shRNA and SPA modules were assessed in a 786-O xenograft model; and AB-2100 potency was measured in a subcutaneous renal A498 xenograft. Results: AB-2100 selectively kills tumors that express both CA9 and PSMA, and not tumors that express CA9 alone, as assessed by in vitro cytotoxicity against single or dual antigen expressing tumor cell lines and by a dual flank xenograft model. Furthermore, we confirmed that co-culture with PSMA-expressing endothelial cells was sufficient to upregulate CA9 CAR expression and enable tumor cell killing. Finally, AB-2100 containing both shRNA-miR and SPA modules demonstrated enhanced anti-tumor activity in xenograft RCC models. Conclusions: These data demonstrate that AB-2100 selectively targets tumors co-expressing PSMA and CA9, and can overcome multiple suppressive mechanisms in the TME. These results support the evaluation of AB-2100 in the clinic for the treatment of advanced or metastatic ccRCC.
IL-6 and PIM1 expression in renal cell carcinoma.
Authors: Kimberly Stephanie Meza, Kimberly Seymour, Stephanie L. Graff, Chadi Nabhan, Andrew Elliott, Sheldon L. Holder
Journal: Journal of Clinical Oncology (2024)

470 Background: Renal cell carcinoma (RCC) is a top ten malignancy in the U.S. Overexpression of the proviral integration site for moloney murine leukemia virus 1 (PIM1) kinase is associated with poor clinical outcomes in RCC patients. PIM1 is a constitutively active serine/threonine kinase promoting cell proliferation, apoptosis resistance, invasion, and migration. The mechanisms underlying PIM1 expression and its function in RCC are not fully delineated. IL-6 is a pleiotropic cytokine that activates the JAK/STAT signaling cascade. High serum IL-6 levels are associated with the poor prognosis of RCC patients and may contribute to RCC invasion and metastasis. STAT3/5 binds directly to the PIM1 promoter inducing PIM1 expression. An IL-6/STAT3/PIM1 axis exists in pancreatic and breast cancer. We previously reported that PIM1 is overexpressed in a panel of human RCC cell lines relative to renal proximal tubule epithelial cells. We also identified that RCC cells secrete IL-6. Our prior studies suggest that differential expression of PIM1 may be linked to autocrine IL-6 signaling. We thus hypothesize that an IL-6/JAK/STAT pathway regulates the expression of PIM1 in RCC. Methods: Retrospective review of DNA (592-gene or whole exome) and RNA (whole transcriptome) NGS data from real-world patient samples profiled at a CLIA-certified lab (Caris Life Sciences). Pathway analysis of differentially expressed genes was assessed using GSEA. Overall survival was calculated from insurance claims data. To understand how IL-6 signaling through the JAK/STAT pathway may regulate PIM1 expression in RCC cells, we examined whether IL-6 blockade using anti-IL-6 antibody or tocilizumab, would modulate PIM1 expression. Similarly, we assessed whether ruxolitinib, and LLL12, a STAT3 inhibitor could regulate PIM1 expression. Results: Transcriptome analyses show that PIM1 expression is significantly increased in metastatic RCC relative to primary RCC. Survival curves demonstrate that PIM1 overexpression is associated with decreased overall survival for RCC patients, independent of treatment received. IL-6 expression was up to 6.5-fold higher in RCC patients with PIM1 overexpression. In RCC cell lines, IL-6 blockade through either anti-IL-6 antibody or tocilizumab was sufficient to decrease PIM1 protein levels. Treatment with ruxolitinib leads to a dose and time-dependent decrease in PIM1 levels. Incubation with a STAT3 inhibitor also resulted in decreased PIM1 levels in RCC cells. Conclusions: These results suggest that differential expression of PIM1 in RCC may be linked to autocrine IL-6 signaling. Furthermore, poor survival in PIM1-overexpressing RCC patients is independent of treatment received, and therefore necessitates use of targeted therapies against this axis. Multiple FDA-approved agents are available that target this pathway. Further investigation is required to determine the efficacy of these agents in pre-clinical models and clinical trials.
Risk of suicide-related deaths (SRD) among patients diagnosed with metastatic genitourinary (mGU) cancers: A retrospective cohort study.
Authors: Ahsan Ayaz, Syed Arsalan Ahmed Naqvi, Manal Imran, Akshat Saxena, Ammad Raina, Kaneez Zahra Rubab Khakwani, Ewan Kemar Cobran, Sajid Ahmad Mir, Parminder Singh, Alan Haruo Bryce, Irbaz Bin Riaz
Journal: Journal of Clinical Oncology (2024)

230 Background: Elevated suicide risk is established in cancer patients compared with the general population. We aim to investigate the risk of SRD among individuals diagnosed with mGU cancers. Methods: Surveillance, Epidemiology, and End Results (SEER) database (2004-2020) was queried to obtain data on suicide death in adults (&gt;20 years of age) diagnosed with mGU cancers including bladder cancer (BC), kidney cancer (KC), and prostate cancer (PC). Standardized mortality ratios (SMRs) with 95% confidence interval (CI) were computed overall and by latency period of &lt;1, 1-5, and &gt;5 years (y) after the initial diagnosis of mGU cancers. SMR &gt;1 indicated increased while &lt;1 indicated decreased SRD. Stratification was done by age (&lt;50y, 50-70y, &gt;70y), race (White, Black, Asian, Native American), ethnicity (Hispanic, non-Hispanic), chemotherapy, radiotherapy, surgery, and marital. Results: This analysis included 87,357 mGU patients. In overall population, the risk of suicide-related deaths was highest &lt;1y after diagnosis (SMR: 3.29, 95% CI: 2.47-4.29) followed by 1-5y (2.61, 2.0-3.35) and &gt;5y (1.27, 0.61-2.34) after diagnosis. With respect to race, SRD was significantly higher in Whites (3.31, 2.46-4.36) but not in Blacks (2.58, 0.31-9.33), and Asians (2.03 (0.05-11.3). In ethnic subgroups, non-Hispanics were observed to have increased SRD (3.71, 2.77-4.86) but not Hispanics (0.83, 0.1-3.0). Patients who received chemotherapy (3.74, 2.10-6.18) or those who did not receive radiotherapy (3.66, 2.68-4.89) were more likely to die from suicide. In terms of marital status, single patients had a higher SRD (4.39, 2.94-6.30) compared to those who were married (2.54, 1.65-3.76). Detailed results are outlined in the Table. Conclusions: Patients with GU malignancies are at increased risk of SRD. Targeted and timely interventions in highest risk subgroups such as Non-Hispanic patients with a recent cancer diagnosis with no partner support, may reduce the risk of SRD in patients diagnosed with mGU cancers. [Table: see text]
Trends in preferred place of death for prostate cancer in the United States from 2003 to 2020: Analysis of CDC WONDER database.
Authors: Karan Jatwani, Mahnoor Sukaina, Atulya Aman Khosla, Rohit Singh, Navpreet Singh, Kamalpreet Singh Walia, Archit Patel, Vasanthan Muthusamy Kumarasamy, Dharmesh Gopalakrishnan
Journal: Journal of Clinical Oncology (2024)

231 Background: Prostate Cancer (PCa) is the most common cancer in men and the second cause of cancer mortality. The identification of the preferred place of death (PPOD) has been shown to improve the delivery of palliative care, reduce healthcare costs, and improve quality of care. We evaluated the trends in PPOD for patients and hospice utilization with PCa in the USA from 2003 to 2020 based on the CDC WONDER (Centers for Disease Control and Prevention for Wide-ranging Online Data for Epidemiologic Research) database. Methods: The US nationwide and state-level data was pooled using the CDC WONDER database from January 01, 2003, to December 31, 2020. The data trends of PPOD for prostate cancer were pooled using the International Classification of Diseases, Tenth Revision as C61: malignant neoplasm of prostate. The analysis of trends in mortality over the past decade was stratified according to age, census region, race, and place of death. Results: The analysis demonstrated that overall mortality due to PCa was 526,783 from 2003 to 2020. Of these deaths, 43,813 (8.32%) were recorded in hospice facilities. The hospice mortality steadily increased from 0.4% in 2003 to the highest of 9.20% in 2019, with a notable decline to 7.6% in 2020. We noticed that the PPOD differed based on racial subgroups. More than half of mortality in the Native American (NA) and African-American (AA) subgroups was observed in a medical facility (51.81% and 58.21%, respectively) compared to Whites (49.15%). Hospice or death at home in NA and AA groups were (48.11% and 41.11%, respectively) compared to Whites (50.85%). The age-stratified mortality analysis revealed increased hospice utilization in 25-44 years (11.95%) vs. 65+ years (8.13%). Upon stratifying the results by census showed the highest hospice utilization in Florida, compared to the lowest in North Dakota (22.6% vs. 0.02%). Conclusions: To our knowledge, this is the first study utilizing the CDC WONDER database to analyze PPOD in PCa-related deaths. We observed a steady increase in hospice utilization from 2003 to 2019 throughout the US, with a decline in 2020, possibly due to the COVID-19 pandemic. The AA and NA groups had higher mortality in medical facilities compared to Whites, whereas the White population utilized more hospice services or died at home. This highlights the existing disparities in end-of-life care in PCa and promotes policy-level changes in the states with lower utilization of hospice services to improve access of care in PCa patients.
Analysis of therapy attrition and changes in outcomes over time for patients (pts) with advanced urothelial cancer (aUC) treated at an academic center.
Authors: Kevin R Reyes, Tanya Jindal, Prianka Deshmukh, Xiaolin Zhu, Chien-Kuang Cornelia Ding, Anthony C. Wong, Carissa E Chu, Sima P. Porten, Jonathan Chou, Terence W. Friedlander, Vadim S Koshkin
Journal: Journal of Clinical Oncology (2024)

590 Background: Despite recent advances in treatment (Tx) options for pts with aUC, real world data suggest that &lt;50% of pts starting Tx receive 2 nd line Tx and &lt;15% receive 3 rd line Tx. We hypothesized that aUC pts treated at an academic center would have lower Tx attrition rates which would translate into improved outcomes for pts treated more recently. Methods: We identified pts with aUC treated since 2011 and analyzed pts who received systemic Tx for metastatic disease, including baseline characteristics, Tx lines and outcomes. Date of 1/1/2019 for Tx start was used to divide pts into earlier vs later Tx groups. Overall survival (OS) from Tx start was assessed using Kaplan Meier Method in pts who started Tx &gt;1 year before censor date of 12/31/2022 for survival. Chi-square test and Wilcoxon rank sum test were used to compare proportions and numerical data, respectively. Results: Among 360 pts with aUC, 237 received 1 st line Tx from 09/2011-08/2022. Of 237 pts, 133 (56%) received 2 nd line Tx, 61 (26%) 3 rd line Tx, 30 (13%) 4 th line Tx, and 10 (4%) &gt; 4 Tx. Pts with Tx in the later group (start after 1/2019) had higher ORR with 1 st and 2 nd line Tx (Table) and more NGS testing (87% vs 54%, p&lt;0.001) relative to earlier group. With median follow-up of 29.5 mos, median OS was 24.2 mos (95% CI: 17.4 – 29.7) for all pts. Pts in the later group (Tx started 1/2019-12/2021, n=94) had improved mOS relative to the 134 pts in the earlier group (30.6 vs 17.4 mos, p=0.02) despite similar number of average Tx lines (2.4 vs 2.5). Conclusions: During a decade when significant changes occurred in the aUC Tx landscape, pts treated at an academic center had lower Tx attrition rates than those described in real world settings during a similar timeframe. Notably, pts who started Tx after 1/2019 had improved OS relative to pts who started Tx earlier, despite similar number of average Tx lines. This finding may be driven by higher ORR to 1 st and 2 nd Tx lines in pts treated more recently. Validation in other academic centers and larger cohorts is needed. [Table: see text]
Utilization of genetic counseling and testing for patients with prostate cancer following integration of a genetic counselor into a genitourinary cancer clinic.
Authors: Lindsey Byrne, Mckenna Lewis, Shihua Wang, Steven K. Clinton
Journal: Journal of Clinical Oncology (2024)

343 Background: Individuals with prostate cancer may have a 10-20% chance of harboring genetic markers for inherited risk. It is critical that germline genetic testing (GGT) is integrated into prostate cancer care to improve therapy and promote prevention and early detection for individuals and their families. We hypothesized that embedding a genetic counselor (GC) into a multidisciplinary genitourinary (GU) Cancer Clinic would enhance referrals and subsequent GGT. We created a retrospective and prospective study to evaluate the impact on genetic counseling referrals, genetic risk assessments provided, and GGT frequencies before (2016-2018) and after (2019-2022) GC integration into the GU clinic at The James Cancer Hospital at The Ohio State University. Methods: A chart review of 2,593 individuals with prostate cancer seen in the GU program from 2016 to 2022 was performed. Data was analyzed by the Chi Square test. Results: Only 39 referrals to the cancer genetics program were documented in 2016-2019 with an increase to 367 during 2019-2022, despite the COVID pandemic. During the 2016-2019 period GGT was offered to 28% and completed in 26% of referred individuals, whereas GGT was offered to 77% (P&lt;0.0001) and completed in 64% (P&lt;0.0001) in the subsequent period. Individuals proceeding with genetic counseling and GGT were younger in the initial period and became more broadly based in subsequent years. Black patients represented only 8% of referrals in 2016-2019 but increased to 16% in the subsequent period. Individuals with a family history of prostate cancer (P&lt;0.0001) as well as higher Gleason grade (P&lt;0.0001), stage (P&lt;0.0001), metastatic disease (P&lt;0.0001), and PSA (P=0.0507) were more likely to choose genetic counseling. Conclusions: The integration of a GU focused GC into a multidisciplinary GU Cancer Clinic at an academic program dramatically increased genetic counseling referrals, and a greater proportion of individuals with prostate cancer proceeded with GGT. Future studies will analyze barriers and factors promoting referrals to a GC so that we may continue to offer individuals and their families' evidence-based treatment and prevention options.
Treatment patterns and outcomes by age in metastatic urothelial carcinoma (mUC): A retrospective tertiary cancer center analysis.
Authors: Nishita Tripathi, Georges Gebrael, Kamal Kant Sahu, Ishwarya Balasubramanian, Constance Caparas, Vinay Mathew Thomas, Jessica N. Cohan, Kaitlyn Pelletier, Benjamin L. Maughan, Neeraj Agarwal, Umang Swami, Sumati Gupta
Journal: Journal of Clinical Oncology (2024)

582 Background: Older adults with locally advanced or mUC often do not receive optimal first-line (1L) therapy (Rx) and subsequent treatments (Lara et al. ASCO 2016). There are limited randomized data for age-appropriate Rx in older mUC adults. Through our real-world study, we describe the clinical characteristics, treatment patterns, and outcomes among pts with mUC, comparing older to younger adults receiving 1L systemic Rx. Methods: This retrospective IRB-approved study included pts receiving care between 2014 and 2023 at the University of Utah, Huntsman Cancer Institute, a tertiary care National Cancer Institute-Designated Comprehensive Cancer Center. Eligible pts had a confirmed diagnosis of mUC and received 1L chemotherapy or 1L immunotherapy-based regimens. Based on age at receipt of 1L Rx, pts aged 70 years or above were grouped in the ‘older’ group, while rest were included in the ‘younger’ cohort. Survival and Rx-related outcomes of those enrolled inwere excluded. Overall survival (OS) between the two groups was compared using Kaplan-Meier and Cox Regression analysis. All statistical analyses were implemented in R-Studio (v.4.2). Results: We identified 212 eligible mUC pts (103 older vs. 109 younger). Older pts received more immunotherapy-based Rx in the 1L (52.4% vs 35.7%, p=0.02), were more likely to be (73.6% vs. 45.4%, p&lt;0.001), less likely to receive subsequent lines of Rx (median; range: 0 (0-3) vs 1 (0-5), p=0.005) and had lower clinical trial participation (69.9% vs 81.6%, p=0.04)compared to younger pts. For survival outcomes and treatment-related analysis, 160 patients (72 older vs. 88 younger) undergoing approved standard of care were included. Among mUC treated with 1L chemotherapy (n=108), more pts required dose adjustments in older group (23/43 vs 15/65 younger). Older adults received less number of cycles of chemotherapy (median; range: 4 (0-6) vs 5 (1-12), p= 0.03). Older pts had OS comparable to younger pts (11.2 mos vs. 14 mos, p=0.06). Pts from both age groups had similar rates of Rx-related toxicity and healthcare visits, independent of the type of systemic Rx. Conclusions: Older pts with mUC tend to be cis-ineligible and have lower bone marrow reserve. Nevertheless, select pts can be treated with risk-adjusted regimens of chemotherapy and with immunotherapy with comparable outcomes to younger mUC pts in terms of toxicity and outcomes. Validated tools to predict vulnerabilities and excessive chemotherapy-related toxicity in older adults with mUC are available and may help mitigate toxicity by informing Rx adjustments.
DNA methyl-transferases (DNMTs) as potential therapeutic vulnerability in prostate cancer.
Authors: Hari K. Koul, Mousa Vatanmakanian, Ellen Nogueira Lima, Lakshmi S Chaturvedi, Sweaty K Koul
Journal: Journal of Clinical Oncology (2024)

339 Background: Prostate cancer (PCa) presents a significant health challenge in men, with a substantial number of deaths attributed to resistance to current Androgen Receptor inhibitors, and emergence of CRPC-adeno, CRPC-NEPC and CRPC-DNPC phenotypes. There is an urgent and unmet need for developing new targets for CRPC especially CRPC-NEPC and CRPC-DNPC. Because cellular plasticity plays a central role in transition to NEPC and DNPC, molecular targets that are critical for prostate cancer cellular plasticity could serve as actionable targets in therapy resistance in prostate cancer. In this study we explored potential role of DNA methyl-transferases in prostate cancer therapy resistance. Methods: We analyzed publicly available clinical datasets to investigate expression of DNMTs (DNMT1, DNMT3a, and DNMT3b), and the association between expression of DNMTs, and prostate cancer progression, neuroendocrine features and overall survival. We evaluated effects of DNMT inhibitor [5-aza-2′-deoxycytidine (5AdC)] in short term experiments PCa cell lines to measure cell viability. We performed epigenetic reprograming by culturing PCa cells in sublethal doses of 5AdC over long term and measured cell migration and invasion. Results: Expression of DNMTs (DNMT1, 3a and 3b) is increased during prostate cancer progression, and there is a positive correlation between DNMT (DNMT1, DNMT3a, and DNMT3b) expression and tumor progression (increasing Gleason score) and NEPC score, and a negative correlation between DNMT expression and patient survival. DNMT1, DNMT3a and DNMT3b are expressed in androgen dependent as well as CRPC cell lines. All PCa cell lines were sensitive to DNMT inhibition (5AdC treatment). 5AdC was as effective as enzalutamide in limiting cell growth and proliferation in enzalutamide sensitive LNCaP cells, and sensitized these cells to enzalutamide. Moreover, 5AdC treatment also halted growth and proliferation of CRPC cell lines (PC3 and DU145) and epigenetic reprograming of these cells with 5AdC decreased cell migration and invasion. Conclusions: These results indicate DNMT expression is associated with prostate cancer progression. These studies suggest DMNT activity as a potential therapeutic vulnerability that can be exploited for limiting cellular plasticity, tumor progression, and therapy resistance in prostate cancer. Because DNMT inhibitors are currently approved for other malignancies, addition of these inhibitors to current treatment regiments could be readily explored in PCa.