Combating melanoma resistance by targeting ABL1/2

Active Project Grant Awarded Last action

Award ID
R01CA258751
Recipient
Awarding agency
Obligated
$4,543,427

Award facts

Assistance listing
93.395 Cancer Treatment Research
Completion date 75% complete
Originally
Place of performance
Lexington, KY 40506, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Despite treatment advances over the past decade, five-year survival rates for metastatic melanoma remain low (23%). Braf mutations occur in 50-75% of melanoma, and a combination of braf and MEK inhibitors (BRAFI, MEKI) are effective therapies; however, acquired resistance rapidly develops for most patients. Research over the past decade has identified mechanisms by which melanoma cells develop resistance to braf/MEK inhibitors, but thus far, there are no FDA-approved regimens that reverse BRAFI/MEKI resistance and increase the 5-year survival rate. Here, we demonstrate that the activities of the ABL family of non-receptor tyrosine kinases are potentiated following BRAFI or BRAFI/MEKI resistance, and ABL1/2 drive resistance. Moreover, targeting ABL1/2 with an FDA-approved anti-leukemia drug, nilotinib, dramatically reverses BRAFI/MEKI (DABRAFENIB/TRAMETINIB) resistance, in vivo, inducing prolonged tumor regression. Based on these exciting findings, the central hypothesis of our proposal is that ABL1/2 are key nodes that activate ERK-dependent or -independent pathways to drive BRAFI/MEKI resistance; thus, targeting ABL1/2 may be effective for overcoming resistance and ultimately extending survival for patients with treatment-refractory melanomas. Our long-term, translational goal is to develop a novel regimen to improve the 5-year survival rate for patients with metastatic melanoma. We propose a comprehensive hypothesis-driven experimental design and multi-disciplinary approach. Aim 1 will define mechanisms by which ABL1/2 drive resistance. To achieve our objective, biochemical, molecular biological and cell biological approaches using parental/resistant melanoma cell lines, pharmacological inhibitors/rnai, mass spectrometry, xenograft, GEM, PDX, and syngeneic in vivo approaches, as well as human tissue collected from the clinical trial (aim 3) will be used to test the hypothesis that ABL1/2 drive MAP3K activation of MEK/ERK/MYC (ERK-dependent resistance); induce ERBB2/ERBB3 activation of PI3K/AKT (ERK-independent resistance); and alter immune cell infiltration. In aim 2, conditioned medium from parental/resistant cell lines, CO-culture experiments using in vitro and in vivo models, and serum collected from animals and patients will be used to test the prediction that the ABL1/2-driven secretome contributes to BRAFI/MEKI resistance. Finally, aim 3 is a multi-site, seamless phase I/II clinical trial that tests the safety of combining nilotinib with DABRAFENIB+TRAMETINIB (BRAFI/MEKI) for treatment-refractory patients. Additional endpoints include identifying the recommended phase II dose, initial efficacy (PFS) based on phase II data, PK/PD studies, and initial exploratory biomarker development. Results from these studies not only will increase our understanding for how melanomas resist the effects of BRAFI/MEKI but also will lay the groundwork for a large, multi-center, randomized clinical trial.

Transactions

Action Obligated Date
Amendment $0
Amendment $58,222
Amendment $524,025
Amendment $524,025
Amendment $553,135
Amendment $553,135
Amendment $553,135
Amendment $571,489
Amendment $571,489
Original award $634,772

Subawards

Subrecipient Amount Awarded
The University Of Iowa Per patient reimbursement required to pay for study costs including study staff to enroll subjects, collect and enter data and provide regulatory support for… $117,000
Vanderbilt University Medical Center VUMC investigators, led by Dr. Johnson, will enroll patients to the proposed clinical trial and will perform all prospective monitoring for safety and efficacy,… $95,681
Saint Luke's Hospital Of Bethlehem, Pennsylvania Dr. Wilson serves as the MPI of this proposal and will work with Dr. Plattner and Dr. Kolesar to oversee all aspects of the application, including study design,… $84,049
Vanderbilt University Medical Center VUMC investigators, led by Dr. Johnson, will enroll patients to the proposed clinical trial and will perform all prospective monitoring for safety and efficacy,… $68,109
Saint Luke's Hospital Of Bethlehem, Pennsylvania Dr. Wilson serves as the MPI of this proposal and will work with Dr. Plattner and Dr. Kolesar to oversee all aspects of the application, including study design,… $90,734
Saint Luke's Hospital Of Bethlehem, Pennsylvania $84,049

Quick answers

Who received award R01CA258751?

R01CA258751 was awarded to The University Of Kentucky Research Foundation by National Cancer Institute (National Institutes of Health) on May 23, 2022.

How much is award R01CA258751 worth?

$4,543,427 has been obligated on R01CA258751.

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