Mass General Cancer Center Researchers Present Key Findings at AACR

Leaders from the Mass General Cancer Center, a member of the Mass General Brigham healthcare system, will present research discoveries and outcomes from clinical trials in cancer at the 2024 American Association for Cancer Research (AACR) Annual Meeting, held April 5-10, in San Diego.

AACR brings together leading experts in cancer research to share the latest breakthroughs in cancer science and medicine. Presentations from Mass General Cancer Center investigators will cover a wide range of topics, from clinical studies to cancer biology, screening and early detection, treatment and more.

Below are a few highlights from this year’s presentations. All times are in EST. View a full list of Mass General Cancer Center presentations.

Rapid on-site nucleic acid detection using CRISPR and digital signal processing for portable and integrated cervical cancer screening in low resource settings

When: April 9, 2024, 4:30-8 p.m.

Who: Cesar Castro, MD

What: Addressing the global disparity in cancer care necessitates the development of rapid and affordable nucleic acid (NA) testing technologies. This need is particularly critical for cervical cancer. Molecular detection of human papillomavirus (HPV) has emerged as a highly accurate screening method, surpassing traditional Pap smears. However, implementing this transition in low- and middle-income countries has been challenging due to the high costs and centralized facilities required for current NA tests. Here, Dr. Castro and team present CreDiT (CRISPR Enhanced Digital Testing), an advanced diagnostic system for rapid, on-site NA detection. CreDiT integrates two major technical breakthroughs: 1) a one-pot CRISPR strategy that simultaneously amplifies both target NAs and analytical signals; and 2) a robust fluorescent detection method based on digital communication (encoding/decoding) technology. The team adapted CreDiT for point-of-care HPV screening by designing probes for high-risk HPV genes and oncoprotein mRNAs and developing a portable CreDiT device capable of processing 12 samples. CreDiT demonstrated sensitive detection of cell-derived HPV DNA targets down to single copies and accurately identified HPV types in every clinical cervical brushing specimen (n = 121) we tested. This technology has the potential to facilitate prompt and reliable triaging of high-risk HPV, overcoming pathology bottlenecks and circumventing geographical and socioeconomic barriers to effective cervical cancer screening in resource-limited regions. This work has spearheaded recent screening research efforts in Uganda and Ghana.

KRYSTAL-1: Pooled phase 1/2 efficacy and safety of adagrasib (MRTX849) in combination with cetuximab in patients with metastatic colorectal cancer (CRC) harboring a KRASG12C mutation

When: April 8, 2024, 2:10-2:25 p.m.

Who: Samuel Klempner, MD

What: The abstract for this presentation is embargoed until 11:30am on Monday, April 8.

Improving CAR T cell efficacy in pancreatic cancer using an in vivo CRISPR Cas9 screen

When: April 7, 2024, 4:30-8 p.m.

Who: Marcela Maus, MD, PhD

What: Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable success in the treatment of certain hematologic malignancies. However, efficacy against solid tumors has remained limited and is associated with relatively low T cell persistence. Here, the team performed an in vivo CAR T cell CRISPR screen in pancreatic adenocarcinoma using a curated guide library to identify genes that enhance CAR T cell persistence in vivo. The transcription factor, GATA3, was consistently identified as the most enriched hit across two donor T cells when Mario-CART was recovered at the 2-week timepoint. When compared to control or a depleted hit, GATA3 KO CAR showed early improvements in tumor clearance in vivo. However, relapse occurred at similar timepoints across groups. Findings highlight the dynamic nature of CAR T-tumor interactions. Gene knockouts that confer enhancements may change over time with varying context (such as in vitro vs in vivo conditions). It may be difficult to identify single gene knockouts that enhance CAR-T cell functions across different conditions and over time, but rather it may be necessary to exert more dynamic functional control of CAR T cells to enhance their function in different settings.

TOP1 mutations mediate cross resistance to ADCs in metastatic breast cancer

When: April 8, 2024, 6:05-6:20 p.m.

Who: Rachel Occhiogrosso Abelman, MD

What: Antibody-drug conjugates (ADCs) have improved survival for patients with metastatic breast cancer (MBC). In patients with HER2 negative MBC, two ADCs have FDA approval: sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd), both with topoisomerase-I (topo-I) inhibitor payloads. Given the many other ADCs in development, there is great interest in using ADC after ADC to maximize treatment benefit for patients. However, there is limited understanding regarding resistance mechanisms to ADCs and impact on ADC sequencing. The team conducted a translational study to report the incidence of TOP1 mutations and clinical impact on ADC sequencing. Based on comprehensive plasma-based genotyping, the team identified four distinct TOP1 mutations: S57C, R364H, W401C, G359E, at a frequency of 6.0% (4/67) at the time of disease progression on ADC compared to a frequency of 0.5% described in primary breast cancer in TCGA. Two of the amino acids found to be mutated are known to form direct interactions with the DNA backbone (G359) or the topoisomerase inhibitor itself (R364). This is the first report describing emergence of TOP1 mutations under selective pressure from ADCs and the impact on mediating cross-resistance to ADC after ADC with topo-I inhibitor payloads. Novel ADCs with alternative payloads may potentially be more effective when used sequentially after an ADC with a topo-I inhibitor. Further biomarker research is needed to optimize ADC sequencing for patients with TOP1 mutant MBC.

Analysis of biomarker and outcomes data: 7-year update from COLUMBUS

When: April 9, 2024, 12-3:30 p.m.

Who: Keith Flaherty, MD

What: In the randomized, two-part, phase 3 COLUMBUS study (NCT01909453), encorafenib (enco) + binimetinib (bini)—an approved regimen in the US, EU, and other countries—improved seven-year progression-free survival (PFS) and overall survival (OS) vs vemurafenib (vemu) in patients with BRAF V600E/K-mutant locally advanced unresectable or metastatic melanoma. The team investigated genetic and transcriptional correlates of outcomes in an exploratory biomarker analysis of COLUMBUS Parts 1 and 2. They found that enco + bini showed benefit across molecular subtypes in BRAF V600E/K-mutant melanoma. The contribution of bini was most pronounced in the immune-high cluster. Improved outcomes in this cluster support ongoing trials of combinations with immune checkpoint inhibitors, such as STARBOARD and PORTSIDE.

Dissecting and quantifying pancreatic cancer plasticity using single-cell multiomics, lineage tracing and functional genomics reveals novel mediators of therapy resistance

When: April 9, 2024, 1:39-1:57 p.m.

Who: Arnav Mehta, MD, PhD

What: Pancreatic cancer (PDAC) is a lethal disease in part because tumor cells exist in distinct transcriptional states (e.g. basal/mesenchymal vs. classical/epithelial) with unique phenotypic properties that contribute to tumor growth and treatment resistance. Amongst the most well-described forms of plasticity in human development and cancer is epithelial-mesenchymal plasticity (EMP), which includes epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET). To better understand and quantify the role of EMP in driving treatment resistance of human PDAC, we have developed single-cell multiomic, functional genomic and computational methods applied to patient-derived models and clinical biopsies. Our efforts define a robust experimental and quantitative framework for studying tumor cell plasticity in patient-derived model systems with validation in human patient samples using single-cell and spatial transcriptomics. Collectively, we nominate several regulators that alter the propensity of EMP in PDAC, thus posing a paradigm whereby perturbations may be used to homogenize tumor populations towards treatment-sensitive phenotypes for combination therapy.