Showing papers by "Joan S. Brugge published in 2023"
TL;DR: Wang et al. as mentioned in this paper evaluated the safety, efficacy and effects on the TME of the PARPi tala combined with the PD-L1 inhibitor avelumab in ABC, and assessed the impact of BRCA1/2 status on clinical outcomes.
Abstract:
Background: PARP inhibitors (PARPi) significantly extend progression-free survival (PFS) compared to chemotherapy in pts with BRCA1/2 mutated (BRCA1/2m) ABC, but responses are not durable. PARPi activate the cGAS-STING pathway leading to increased PD-L1 expression and cytotoxic T-cell recruitment, creating a tumor microenvironment (TME) that may be more vulnerable to immunotherapy. This study was conducted to evaluate the safety, efficacy and effects on the TME of the PARPi tala combined with the PD-L1 inhibitor avelumab in ABC, and to assess the impact of BRCA1/2 status on clinical outcomes.
Methods: TALAVE was an open-label, multi-institutional trial (NCT03964532) for pts with HER2-negative ABC. Pts were enrolled in two cohorts: cohort 1 - BRCA1/2m and HER2-negative ABC; cohort 2 - BRCA1/2 wildtype TNBC. Pts received a 4-week induction of tala (1mg po daily D1-D28), followed by a combination of daily tala and avelumab (800mg IV D1, D15). The primary objective was the safety and tolerability of the combination. Secondary objectives included ORR, OS and PFS. Pts underwent serial biopsies to investigate molecular signatures associated with BRCA status or clinical benefit using multiple omics techniques: RNA profiling by NanoString PanCancer IO 360™ Panel, GeoMx® Digital Spatial Profiler (DSP) Whole Transcriptome Atlas (WTA) and protein spatial analysis by multiplex immunofluorescence (mIF) and Cyclic Immunofluorescence (CyCIF).
Results: 12 pts were enrolled in each cohort. In cohort 1, 5 pts had gBRCA1, 6 had gBRCA2 and 1 had sBRCA2 mutation. The median age was 50 [IQR:43-59.5]; all pts were female, with median of 1 prior therapy for ABC [IQR: 0-2.5]. 42% pts had prior platinum. ORR was 42% (83% in cohort 1; 0% in cohort 2). There were 10 PRs, all in cohort 1. mPFS was 5.1 months (mo) (95% CI: 3.7-7.3 mo); 9.3mo in cohort 1 and 2.9mo in cohort 2. 5 out of 24 pts remain on treatment, all in cohort 1. Treatment related adverse events (TRAEs) included anemia 33%, neutropenia 25% (gr3+ 13%), thrombocytopenia 21% (gr3+ 13%), fatigue 33% and nausea 29%. Other TRAEs gr3+ included dyspnea (4%) and AST elevation (4%). There were no gr5 events. RNA analysis showed that in cohort 1, tala monotherapy disrupted MMEJ, induced antiproliferative effects and expression of genes in the cGAS-STING pathway, including TBK1-mediated IRF3 activation, with downstream induction of T-cell, dendritic cell and cytokine gene expression. These effects were not seen in biopsies post tala monotherapy in cohort 2. mIF analyses demonstrated T-cell and macrophage infiltration in BRCA1/2m tumors. Analyses of post-combination biopsies is ongoing.
Conclusions: There were no new safety signals of PARPi combined with immunotherapy. Responses were limited to pts with BRCA1/2m. RNA and protein analyses indicate cGAS-STING activation and immune cell infiltration in BRCA1/2m tumors, validating murine preclinical findings.
Citation Format: Filipa Lynce, Kenichi Shimada, Xue Geng, Edward T. Richardson, Candace Mainor, Mei Wei, Julie M. Collins, Paula P. Pohlmann, Arielle L. Heeke, Kelly F. Zheng, Madeline Townsend, Jane Staunton, Stuart J. Schnitt, Joan S. Brugge, Hongkun Wang, Claudine Isaacs, Geoffrey I. Shapiro, Jennifer L. Guerriero. TALAVE: Induction talazoparib (tala) followed by combined tala and avelumab in patients (pts) with advanced breast cancer (ABC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT142.
TL;DR: In this article, a fully humanized anti-CLDN6 antibody was conjugated to a monomethyl auristatin E (MMAE) via a cleavable linker, resulting in the potential therapeutic ADC, CLDN6-23-ADC.
Abstract: Abstract Purpose: Claudin-6 (CLDN6) is expressed at elevated levels in multiple human cancers including ovarian and endometrial malignancies, with little or no detectable expression in normal adult tissue. This expression profile makes CLDN6 an ideal target for development of a potential therapeutic antibody–drug conjugate (ADC). This study describes the generation and preclinical characterization of CLDN6–23-ADC, an ADC consisting of a humanized anti-CLDN6 monoclonal antibody coupled to monomethyl auristatin E (MMAE) via a cleavable linker. Experimental Design: A fully humanized anti-CLDN6 antibody was conjugated to MMAE resulting in the potential therapeutic ADC, CLDN6–23-ADC. The antitumor efficacy of CLDN6–23-ADC was assessed for antitumor efficacy in CLDN6-positive (CLDN6+) and -negative (CLDN6−) xenografts and patient-derived xenograft (PDX) models of human cancers. Results: CLDN6–23-ADC selectively binds to CLDN6, versus other CLDN family members, inhibits the proliferation of CLDN6+ cancer cells in vitro, and is rapidly internalized in CLDN6+ cells. Robust tumor regressions were observed in multiple CLDN6+ xenograft models and tumor inhibition led to markedly enhanced survival of CLDN6+ PDX tumors following treatment with CLDN6–23-ADC. IHC assessment of cancer tissue microarrays demonstrate elevated levels of CLDN6 in 29% of ovarian epithelial carcinomas. Approximately 45% of high-grade serous ovarian carcinomas and 11% of endometrial carcinomas are positive for the target. Conclusions: We report the development of a novel ADC, CLDN6–23-ADC, that selectively targets CLDN6, a potential onco-fetal-antigen which is highly expressed in ovarian and endometrial cancers. CLDN6–23-ADC exhibits robust tumor regressions in mouse models of human ovarian and endometrial cancers and is currently undergoing phase I study.
TL;DR: Brugge et al. as mentioned in this paper discussed different types of non-genetic, reversible mechanisms that confer therapy resistance, those involving immediate adaptive responses to stresses associated with therapies, and the other states associated with longer term persistence.
Abstract:
Despite favorable initial response to therapy, many cancer patients develop recurrent disease and succumb to it within five years of diagnosis. While there has been much progress in characterizing the pathways that contribute to stable genetic drug resistance, non-genetic mechanisms have recently emerged as important drivers of therapy failure in cancer. In my presentation, I will discuss different types of non-genetic, reversible mechanisms that confer therapy resistance, those involving immediate adaptive responses to stresses associated with therapies, and the other states associated with longer term persistence. I will include a discussion of strategies to target the vulnerabilities associated with each of these adaptive responses.
Citation Format: Joan Brugge. Drug-tolerant persister cells in cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr WS2-1.
TL;DR: A first basic description of the nature of FT stem cells and their molecular requirements for self-renewal, paving the way for mechanistic work investigating the role of stem cells in FT health and disease is proposed.
Abstract: Despite its significance to reproduction, fertility, sexually transmitted infections and various pathologies, the fallopian tube (FT) is relatively understudied. Strong evidence points to the FT as the tissue-of-origin of high grade serous ovarian cancer (HGSOC), the most fatal gynaecological malignancy. HGSOC precursor lesions arise specifically in the distal FT (fimbria) which is reported to be enriched in stem-like cells. Investigation of the role of FT stem cells in health and disease has been hampered by a lack of characterization of FT stem cells and lack of models that recapitulate stem cell renewal and differentiation in vitro. Using optimized organoid culture conditions to address these limitations, we found that FT stem cell renewal is highly dependent on WNT/β-catenin signaling and engineered endogenous WNT/β-catenin signaling reporter organoids to biomark, isolate and characterize putative FT stem cells. Using functional approaches as well as bulk and single cell transcriptomic analyses, we show that an endogenous hormonally-regulated WNT7A-FZD5 signaling axis is critical for self-renewal of human FT stem cells, and that WNT/β-catenin pathway-activated FT cells form a distinct transcriptomic cluster of cells enriched in ECM remodelling and integrin signaling pathways. In addition, we find that the WNT7A-FZD5 signaling axis is dispensable for mouse oviduct regeneration. Overall, we provide a deep characterization of FT stem cells and their molecular requirements for self-renewal, paving the way for mechanistic work investigating the role of stem cells in FT health and disease. GRAPHICAL ABSTRACT
TL;DR: Leshchiner et al. as discussed by the authors performed a comprehensive characterization of residual cancer cells that survive neoadjuvant treatment in serous ovarian cancer and can give rise to future recurrences.
Abstract:
Drug resistance and disease recurrence represent a major obstacle in the treatment of high-grade serous ovarian cancer (HGSOC). Here, we performed a comprehensive characterization, at the single-cell level, of residual (persister) cancer cells that survive neoadjuvant treatment in HGSOC and can give rise to future recurrences. We aim to understand the adaptive responses that enable persistence and the key pathways that underlie them to find new targets for combination therapy with the ultimate goal of eradicating all tumor cells. We collected 27 tumor samples (16 pre-treatment and 11 post-neoadjuvant carboplatin/taxol samples, with multi-site sampling per patient) for single-cell RNA sequencing (scRNA-Seq). To complement the patient-derived dataset and model the time course of drug persistence, we performed scRNA-Seq of 13 distinct ovarian cancer cell lines treated with chemotherapy in vitro for a series of time points up to 28 days.
We performed single-cell gene expression and copy number analyses of patient samples, annotated detailed cell types, and detected multiple immune cell populations, the majority of which maintained a highly immunosuppressive program both in untreated and treated samples. Remarkably, we detected a rare population of cancer cells that differed dramatically in their transcriptional program. These cells exhibited high expression of components of motile cilia and the transcription factor FOXJ1, a master regulator of ciliogenesis. We validated the presence of FOXJ1+ cells in patient samples by immunohistochemistry and immunofluorescence. Ciliated cells were enriched in the post-treatment vs. pre-treatment samples, suggesting a possible role in drug persistence. We are now experimentally testing the role of the FOXJ1-driven transcriptional program in mediating drug resistance.
To systematically identify transcriptional programs activated in persister cells, we performed differential expression analysis on pre- vs. post-treatment samples. We identified previously implicated mechanisms of drug resistance, such as the Epithelial-Mesenchymal Transition and the antiapoptotic response driven by MCL1. We additionally detected upregulation of the metallothionein family of genes, which may represent a mechanism of resistance to platinum-based compounds. We detected potentially novel mechanisms representing a stress response signature driven by JUND, an interferon gamma signature, and a pro-stem cell signature characterized by LGR5 expression. Independently, our analysis of the ovarian cancer cell lines treated with taxol in vitro confirmed the JUND transcriptional program as potentially driving ovarian cancer persistence. Our study will help reveal pathways enabling ovarian cancer cells to persist through treatment and, ultimately, could lead to novel approaches for targeting persistence and achieving deeper therapeutic responses.
Citation Format: Elizaveta Leshchiner, Richard Panayiotou, Anay Gupta, Thomas Zhang, Kayli Neil, Nomeda Girnius, Aylin Henstridge, Brian P. Danysh, Ignaty Leshchiner, Sarah J. Hill, Laxmi Parida, Ursula A. Matulonis, Joan S. Brugge, Gad Getz. Drug persistence pathways in ovarian cancer identified by single-cell analysis of patient samples and cell line models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3459.