Dr. Varkaris is a physician scientist at the Mass General Cancer Center and a dedicated member of the Termeer Center for Targeted Therapies. His career has been marked by a dual commitment to direct patient care and pioneering translational research. Half of his efforts are devoted to administering early clinical trials of investigational agents targeting growth factor receptor signaling (FGFR2, PIK3CA and KRAS) and apoptosis, while the remaining time is focused on unraveling mechanisms of resistance to these agents and developing rational combination therapies that may benefit patients.
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Medical Education
American Board Certifications
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Selected publications:
1. Varkaris A, Fece de la Cruz F, Martin EE, Norden BL, Chevalier N, Kehlmann AM, Leshchiner I, Barnes H, Ehnstrom S, Stavridi AM, Yuan X, Kim JS, Ellis H, Papatheodoridi A, Gunaydin H, Danysh BP, Parida L, Sanidas I, Ji Y, Lau K, Wulf GM, Bardia A, Spring LM, Isakoff SJ, Lennerz JK, Del Vecchio K, Pierce L, Pazolli E, Getz G, Corcoran RB, Juric D. Allosteric PI3Ka Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations. Cancer Discov. 2024 Feb 8;14(2):227-239. doi: 10.1158/2159-8290.CD-23-0704. PubMed PMID: 37916958; PubMed Central PMCID: PMC10850944.
In this study, we leveraged a decade's worth of clinical data, comprehensive genomic analyses, and the largest tumor-autopsy program to understand mechanisms of resistance to FDA approved PIK3CA inhibitors. Our work defined the clinical landscape of acquired resistance to FDA-approved PI3Ka orthosteric inhibitors. We discovered that genomic alterations within the PI3K pathway are a significant mode of resistance and identified a new class of secondary PIK3CA resistance mutations that can be targeted by an allosteric PI3Ka inhibitor. This groundbreaking study redefined the clinical approach to patients treated with orthosteric PIK3CA inhibitors and demonstrated the potential sensitivity of a subset of tumors to further pathway inhibition (novel PIK3CA, AKT or MTOR inhibition).
2. Varkaris A, Pazolli E, Gunaydin H, Wang Q, Pierce L, Boezio AA, Bulku A, DiPietro L, Fridrich C, Frost A, Giordanetto F, Hamilton EP, Harris K, Holliday M, Hunter TL, Iskandar A, Ji Y, Lariv?e A, LaRochelle JR, Lescarbeau A, Llambi F, Lormil B, Mader MM, Mar BG, Martin I, McLean TH, Michelsen K, Pechersky Y, Puente-Poushnejad E, Raynor K, Rogala D, Samadani R, Schram AM, Shortsleeves K, Swaminathan S, Tajmir S, Tan G, Tang Y, Valverde R, Wehrenberg B, Wilbur J, Williams BR, Zeng H, Zhang H, Walters WP, Wolf BB, Shaw DE, Bergstrom DA, Watters J, Fraser JS, Fortin PD, Kipp DR. Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Ka Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia. Cancer Discov. 2024 Feb 8;14(2):240-257. doi: 10.1158/2159-8290.CD-23-0944. PubMed PMID: 37916956; PubMed Central PMCID: PMC10850943.
The ReDiscover Trial showed that RLY-2608 has a favorable toxicity profile compared to orthosteric inhibitors and promising early clinical efficacy. Our integration of preclinical and clinical data provided proof-of-concept for mutant-selective PIK3CA inhibition in solid tumors, achieving potent and durable tumor responses without the side effects associated with PIK3CA WT inhibition.
3. Nouri M, Varkaris A, Ridinger M, Dalrymple SL, Dennehy CM, Isaacs JT, Einstein DJ, Brennen WN, Balk SP. AKT Inhibition Sensitizes to Polo-Like Kinase 1 Inhibitor Onvansertib in Prostate Cancer. Mol Cancer Ther. 2024 Jun 19;. doi: 10.1158/1535-7163.MCT-23-0933. [Epub ahead of print] PubMed PMID: 38894678.
In this preclinical work, we used non-biased comprehensive drug screening and patient derived models to identify PLK-1 inhibitor-based combination therapies that may be beneficial for prostate cancer patients. We found that combined inhibition of PLK1 and AKT causes strong growth inhibition and apoptosis in a subset of prostate cancer models. These results have set the stage for clinical evaluation of this drug combination.
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