Date of Award

January 2022

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Keith A. Choate

Second Advisor

Michael Girardi

Abstract

Cutaneous T cell lymphoma (CTCL) is a skin-homing non-Hodgkin lymphoma, ofteninvolving the blood and lymph nodes in advanced stages. Complete responses to advanced CTCL current therapies are rare. A characteristic hallmark of CTCL that poses therapeutic challenges is the genetic diversity of malignant T-cell populations and lack of classic driver mutations present in other lymphomas; however, we hypothesize that common key aberrant pathways contribute to disease burden and that these can be overcome with synergistic drug combination strategies that simultaneously uncouple these pathways in CTCL. We previously reported that first-generation JAK1/2 inhibitor ruxolitinib synergistically potentiates venetoclax (BCL2 inhibitor), vorinostat (HDAC inhibitor), and mivebresib (BET inhibitor) in advanced CTCL. Characterizing the broader applicability of JAK inhibitors in CTCL and their potential use in combination therapies is crucial for informing our future analyses of dysregulations in CTCL JAK/STAT signaling and how these interactions with other aberrant networks can be therapeutically exploited. To this end, we performed in vitro CTCL patient-derived cell viability assays against a panel of agents exhibiting different JAK family member selectivity profiles, singly and in combination with BCL2, HDAC, and BET inhibitors. Patients were more sensitive to JAK2-selective vs. JAK2/3-selective (p=0.008), JAK1/2-selective (p<0.00001) and pan-JAK1/2/3 inhibitors (p<0.00001). Established CTCL cell lines exhibited varied responses to JAK-inhibitors and were also more sensitive to JAK2- selective agents vs. pan-JAK1/2/3 inhibitory agents (p<0.0032). Combination drug screenings with JAK2-selective inhibitors and BCL2, HDAC, or BET inhibitors exhibited varying degrees of capacity for synergy. These functional-level screenings inform exploration of strategic combination formulation and lay the groundwork for analysis of the interplay between key dysregulated pathways in CTCL.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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