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Frederick Wilson, MD, PhD

Assistant Professor

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Frederick Wilson, MD, PhD
Yale Medicine

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Research Summary

Dr. Wilson's research focuses on the identification and characterization of genetic vulnerabilities in cancer as well as genetic determinants of sensitivity and resistance to targeted therapies. His group leverages functional genomic approaches in cell models and sequencing-based characterization of patient tumors to understand how cancers become resistant to targeted therapies and to identify new potential treatment targets.

Extensive Research Description

Dr. Wilson's research efforts broadly include cancer genomics, identifying cancer vulnerabilities, and understanding resistance to targeted therapies. Specific areas of interest include:

1. Characterization of RASGRF1 fusions as an oncogenic driver in lung and other cancers. Dr. Wilson’s team identified recurrent gene fusions involving the guanine exchange factor (GEF) RASGRF1 in non-small cell lung cancer, pancreatic ductal adenocarcinoma, and sarcoma. RASGRF1 fusions activate RAS signaling, induce cellular transformation, and promote tumorigenesis. Preclinical studies demonstrate that tumor cells harboring RASGRF1 fusions are sensitive to targeting of the MAP kinase pathway, an established downstream effector of RAS signaling.

2. PRMT5 pathway inhibition as a therapeutic strategy in cancers with MTAP loss. Deletion of the MTAP gene occurs in approximately 15% of all malignancies. Dr. Wilson and others identified the arginine methyltransferase PRMT5 as a potential genetic vulnerability in cancers with MTAP loss, suggesting that these cancers may be sensitive to targeting of PRMT5. This work provided a rationale for the development of inhibitors of PRMT5 and MAT2A (another pathway component) which are entering early-phase clinical study in patients with advanced MTAP-deleted cancers.

3. Resistance to targeted therapies in lung cancer. Multiple FDA-approved targeted therapies are available for patients with advanced non-small cell lung cancer with mutated oncogenic drivers including EGFR, ALK, and ROS1. Unfortunately, resistance to these therapies is common and limits the ability to provide durable cancer control for patients. Using a genome-scale functional genomic screening platform, Dr. Wilson identified novel genetic drivers of resistance to ALK inhibitors in ALK-dependent lung cancer models. Many of the resistance-associated genes identified from this study also confer resistance to EGFR inhibition in EGFR-mutant lung cancer models. Insights from these studies may inform the development of treatment paradigms to delay or overcome resistance to targeted therapies in patients with advanced lung cancers.

Ultimately, translational research efforts in the laboratory are directed towards the identification of novel drug targets and opportunities for therapeutic drug combinations to overcome or delay drug resistance.

Coauthors

Research Interests

Lung Neoplasms

Selected Publications

Clinical Trials

ConditionsStudy Title
LungRandomized Phase III Study of Combination Osimertinib (AZD9291) and Bevacizumab Versus Osimertinib (AZD9291) Alone as First-Line Treatment for Patients With Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)
LungA Phase II Study of AMG 510 in Participants With Previously Treated Stage IV or Recurrent KRAS G12C Mutated Non-Squamous Non-Small Cell Lung Cancer (ECOG-ACRIN LUNG-MAP SUB-STUDY)
LungIntegration of Immunotherapy Into Adjuvant Therapy for Resected NSCLC: ALCHEMIST Chemo-IO (ACCIO)
LungThe Study of NC318 Alone or in Combination With Pembrolizumab in Patients With Advanced Non-small Cell Lung Cancer
Liver; Lung; Melanoma, skin; Other Female GenitalPhase 2 Trial of Voyager V1 in Combination With Cemiplimab in Patients With Hepatocellular Carcinoma, Non-Small Cell Lung Cancer, Melanoma or Endometrial Carcinoma
Lung; StomachA Phase 1b, Protocol Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 510 (pINN) Sotorasib Monotherapy and in Combination With Other Anti-cancer Therapies in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101)
LungPhase IB/II Trial Of Dose-Deescalated 3-Fraction Stereotactic Body Radiotherapy For Centrally Located Lung Cancer
LungLUNGMAP: A Master Protocol To Evaluate Biomarker-Driven Therapies And Immunotherapies In Previously-Treated Non-Small Cell Lung Cancer (Lung-Map Screening Study)
LungA Phase III Double-Blind Trial for Surgically Resected Early Stage Non-small Cell Lung Cancer: Crizotinib Versus Placebo for Patients With Tumors Harboring the Anaplastic Lymphoma Kinase (ALK) Fusion Protein
LungAdjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALCHEMIST)
Brain and Nervous System; Lung; Melanoma, skinA Phase II Trial of Pembrolizumab Plus Bevacizumab in Patients With Metastatic Melanoma or Non-small Cell Lung Cancer With Untreated Brain Metastases
LungA Phase III, Double-blind, Placebo-controlled, Randomised, Multicentre, International Study of Durvalumab Plus Oleclumab and Durvalumab Plus Monalizumab in Patients With Locally Advanced (Stage III), Unresectable Non-small Cell Lung Cancer (NSCLC) Who Have Not Progressed Following Definitive, Platinum-Based Concurrent Chemoradiation Therapy
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