Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies

Abstract

In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.

Single-Cell Proteomics Analysis of Recurrent Low-Grade Serous Ovarian Carcinoma and Associated Brain Metastases

“…To characterize the evolution in the tumor composition during progression from a localized tumor to brain metastasis, single-cell proteomics analysis was performed using multiplex Cyc-IF, as previously described ( 17 ). By performing sequential cycles of staining, imaging, and quenching, Cyc-IF allowed the visualization and spatially oriented analysis of 42 proteins at the single-cell level in a single tissue slide of each sample ( 19 ) ( Figure 1C ).…”

“…Cyclic immunofluorescence (Cyc-IF) was performed as previously described by our group ( 17 ). Briefly, Cyc-IF allows the detection and spatial single-cell analysis of more than 40 proteins on a single Formalin-Fixed Paraffin-Embedded (FFPE) slide.…”

PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors

“… 67 Future studies could focus on deeper characterization of the immune microenvironment in patients using additional protein or nucleic acid approaches. 68 …”

The Human Tumor Atlas Network’s beginning steps toward the future of collaborative multi-omic discovery

“…In addition to demonstrating the potential of the HTAN, the investigators illustrate another paradigm for accelerated discovery, the Serial Measurements of Molecular and Architectural Responses to Therapy (SMAART) clinical trial. 6 , 7 , 8 The goal of this trial is to utilize multi-omic data to guide therapy for individual patients, with clinical decision-making aided by a multi-disciplinary molecular tumor board. As an early participant of SMAART, the featured patient was treated with precision therapies that are not yet part of the standard-of-care armamentarium for hormone-receptor-positive breast cancer, including novel chemotherapy/immunotherapy combinations, anti-androgen agents (enzalutamide), and dasatinib.…”