R01CA265929

Pacritinib in Rel/Refr T-Cell Lymphomas - Project Abstract

The T-cell lymphomas (TCL) are an area of unmet medical need as patients, particularly those with relapsed or refractory disease, are rarely cured with existing therapies. We, and others, have shown that antigen-, costimulation-, and cytokine-dependent signaling cooperatively promote the growth and survival of malignant T cells and confer their resistance to conventional chemotherapy. These signaling cascades are propagated by highly recurrent gain-of-function mutations in relevant kinases and by exogenous ligands provided by constituents of the tumor microenvironment (TME), including lymphoma-associated macrophages (LAM).

Early phase clinical trials investigating tyrosine-kinase inhibitors (TKI) selective for relevant targets have been completed (or are ongoing), but most responses observed with these agents are partial and rarely durable. The genetic and molecular heterogeneity associated with the TCL and the cooperativity (and partial redundancies) among signaling pathways may explain the suboptimal activity associated with many targeted agents.

Constituents of the TME, particularly LAM, create a niche that promotes TCL growth and survival both directly, by providing exogenous ligands for TCL-associated antigen, costimulatory, and cytokine receptors, and indirectly by suppressing host anti-tumor immunity. Therefore, an alternative, and potentially complementary, therapeutic approach is to target LAM.

Efforts to deplete tumor-associated macrophages have been largely devoted to colony-stimulating factor-1 receptor (CSF-1R) antagonists, as current dogma suggests that this is the dominant homeostatic cytokine required for the survival of tissue resident macrophages. However, our own preliminary data challenges this conception, at least in a TCL context. Pexidartinib, for example, is a selective, and FDA-approved, CSF-1R TKI, to which TCL-associated macrophages are largely resistant.

As LAM play a central role in TCL pathogenesis, one of our long-term goals is to develop novel, targeted therapies that impair their expansion, survival, and functional polarization. With that goal in mind, we performed an unbiased, high-throughput screen with almost 200 targeted agents and discovered that TCL-associated macrophages, while resistant to multiple selective CSF-1R antagonists, were highly sensitive to pacritinib.

Pacritinib is a safe, well-tolerated, oral Janus family kinase (JAK) inhibitor that has been investigated in multiple phase I, II, and III studies (largely in myeloproliferative neoplasms). In addition to inhibiting multiple JAKs (JAK2, TYK2, JAK3), we have shown that pacritinib inhibits CSF-1R and SRC family kinases at clinically achievable concentrations, both of which are highly relevant targets in TCL.

Therefore, our overarching premise is that inhibition of multiple, highly relevant kinases with both cell-autonomous and non-cell-autonomous roles in TCL pathogenesis is an attractive, but largely unexplored, therapeutic strategy that warrants further investigation. Our overall objectives in this application are to examine the efficacy of pacritinib and interrogate relevant predictive and pharmacodynamics biomarkers in an investigator-initiated, multicenter, phase II clinical trial.

Regents Of The University Of Michigan

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Ann Arbor, Michigan 481091276 United States

Single Zip Code

National Cancer Institute's Investigator-Initiated Early Phase Clinical Trials for Cancer Treatment and Diagnosis (R01 Clinical Trials Required) (PAR-18-560)

Amendment Since initial award the End Date has been extended from 08/31/26 to 08/31/27 and the total obligations have increased 395% from $645,497 to $3,194,893.