New platform optimizes selection of combination cancer therapies

The findings were presented today at the American Association for Cancer Research (AACR) Annual Meeting 2022 by principal investigator Anil Korkut, Ph.D., assistant professor of Bioinformatics and Computational Biology. The study results also were published today in Cancer Discovery.

The platform, called REcurrent Features LEveraged for Combination Therapy (REFLECT), integrates machine learning and cancer informatics algorithms to analyze biological tumor features -- including genetic mutations, copy number changes, gene expression and protein expression aberrations -- and identify frequent co-occurring alterations that could be targeted by multiple drugs.

"Our ultimate goal is to make precision oncology more effective and create meaningful patient benefit," Korkut said. "We believe REFLECT may be one of the tools that can help overcome some of the current challenges in the field by facilitating both the discovery and the selection of combination therapies matched to the molecular composition of tumors."

Targeted therapies have improved clinical outcomes for many patients with cancer, but monotherapies against a single target often lead to treatment resistance. Cancer cells frequently rely on co-occurring alterations, such as mutations in two signaling pathways, to drive tumor progression. Increasing evidence suggests that identifying and targeting both alterations simultaneously could increase durable responses, Korkut explained.

Led by Korkut and postdoctoral fellow Xubin Li, Ph.D., the researchers built and used the REFLECT tool to develop a systematic and unbiased approach to match patients with optimal combination therapies.

Using REFLECT, they analyzed pan-cancer datasets from both MD Anderson and publicly available sources, including pre-treatment patient tumor samples, cell lines and patient-derived xenografts (PDXs), representing more than 10,000 patients and 33 cancer types. This generated 201 patient cohorts, each defined by a single therapeutically actionable biomarker, such as EGFR mutation or PD-L1 overexpression.

Within each cohort, the team generated REFLECT signatures of additional alterations that may be actionable therapeutic targets, thus pointing to sub-cohorts that may benefit from specific combination therapies. Across all cohorts, the researchers identified a total of 2,166 combinations, with at least one Food and Drug Administration-approved agent, matched to co-occurring alterations. In total, 45% of the patients included in the initial analysis were matched to at least one combination therapy.

The researchers validated the REFLECT approach through retrospective analysis of publicly available pre-clinical and clinical studies, comparing REFLECT-matched combinations used in those trials to combinations not matched by the tool.

In pre-clinical trials with PDX models, REFLECT-matched combinations had a 34.5% decrease in median tumor volume, while non-matched combinations had a 5.1% increase. Similarly, progression-free survival (PFS) was higher with matched combinations. The researchers also demonstrated a higher synergy score in REFLECT combinations relative to others, defined using the highest single agent (HSA) model.

The researchers also retrospectively validated the approach in the clinical setting through available data from the I-PREDICT trials, which evaluated many combination therapies across diverse cancer types. Patients in this trial that received combinations predicted by REFLECT to be most beneficial had significantly longer PFS and overall survival compared to other combinations.

In this study, the team also developed a detailed map of oncogenic alterations that co-exist with specific immune features. This map revealed many common alterations that frequently co-occur with immunotherapy response markers, such as defects in DNA damage repair and changes in the levels of specific epigenetic regulators. The findings suggest that therapies targeting these pathways should be further studied as options to improve immunotherapy responses.

"While REFLECT is still a concept that requires additional validation, we anticipate a great opportunity to translate this work into real clinical benefits," Korkut said. "In the future, multi-omic profiles from pre-treatment patient samples could be loaded to the REFLECT pipeline to generate co-alteration signatures, allowing physicians to consider precision combination therapies tailored to molecular profiles of those patients."

In the future, this approach will benefit from improved informatics resources to better match therapies to alterations at the RNA and protein level, Korkut explained. Additionally, the researchers plan to expand their study to better address and predict toxicity from matched drug combinations. Finally, future studies also will seek to address the significant heterogeneity within tumors, which can affect response to targeted therapies.

The research was supported by the National Institutes of Health/National Cancer Institute (P30 CA016672, U01 CA253472-01A1, 5UL1TR003167-02, 7R01CA206025-06), the Ovarian Cancer Research Alliance Collaborative Research Award, the Innovation in Cancer Informatics Fund, the Cancer Prevention and Research Institute of Texas (CPRIT) (RP170640), MD Anderson's Colorectal Cancer Moon Shot^®, the Department of Defense (W81WH-18-1-0678), the National Resource for Network Biology, and the National Institute of General Medical Sciences (GM103504)

In addition to Korkut and Li, additional MD Anderson authors include: Gonghong Yan, Ph.D., Zeynep Dereli, Ph.D., and Behnaz Bozorgui, Ph.D., all of Bioinformatics and Computational Biology; Parisa Imanirad, Ph.D., of Systems Biology; David Menter, Ph.D., and Scott Kopetz, M.D., Ph.D., both of Gastrointestinal Medical Oncology; Patrick G. Pilié, M.D., of Genitourinary Medical Oncology; and Timothy Yap, M.B.B.S., Ph.D., of Investigational Cancer Therapeutics. Collaborating authors include: Elisabeth Dowling, Ph.D., of Rice University, Houston; Jacob Elnaggar, of Louisiana State University Health Sciences Center, New Orleans; Augustin Luna, Ph.D., of Dana-Farber Cancer Institute, Boston; and Chris Sander, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.