Not listed
BIOMARKER-DRIVEN STRATEGIES TO OVERCOME IMMUNOTHERAPY RESISTANCE IN STK11-DEFICIENT NSCLC - SUMMARY DESPITE SIGNIFICANT ADVANCES IN IMMUNO-ONCOLOGY (IO) TREATMENTS, LUNG CANCERS WITH LOSS-OF-FUNCTION MUTATIONS IN STK11, COMPRISING 20-30% OF CASES, DEMONSTRATE POOR PROGNOSIS DUE TO RESISTANCE TO THESE STRATEGIES. OUR PROPOSAL TARGETS THE INTERACTION BETWEEN SPECIFIC TUMOR 'DIFFERENTIATION PHENOTYPES' AND IMMUNE RESISTANCE PATHWAYS, ASSOCIATED WITH STK11-DEFICIENT LUNG CANCERS. FIRSTLY, WE'VE FOUND THAT THESE DIFFERENTIATION PHENOTYPES DRASTICALLY INFLUENCE THE IMMUNE COMPOSITION OF THE TUMOR MICROENVIRONMENT (TME) AND THE PATIENT'S RESPONSE TO IMMUNE CHECKPOINT BLOCKADE (ICB). FURTHERMORE, WE'VE DEVELOPED STK11-MLDD, A NOVEL BIOMARKER THAT MEASURES THESE DIFFERENTIATION PHENOTYPES AND MAY PREDICT ICB BENEFIT. SECONDLY, WE'VE IDENTIFIED THE IMMUNE REGULATOR TRAF2 AND ITS PARTNER CIAP1 AS PROMOTERS OF IMMUNE RESISTANCE, SPECIFICALLY IN THE CONTEXT OF STK11 DEFICIENCY, AND APPEAR TO BE LINKED TO THE NEUROENDOCRINE DIFFERENTIATION PHENOTYPE. THESE FINDINGS PROVIDE THE FOUNDATION FOR OUR TWO COMPLEMENTARY AIMS. AIM 1 FOCUSES ON CHARACTERIZING THE INTERACTION BETWEEN TUMOR DIFFERENTIATION PHENOTYPES, CORRESPONDING IMMUNE TME PHENOTYPES, AND CLINICAL RESPONSE TO ICB. WE'LL VALIDATE THE STK11-MLDD BIOMARKER IN MULTIPLE PATIENT COHORTS AND DEVELOP IT AS A CLINICAL TOOL FOR FUTURE TRIALS. ADDITIONALLY, USING FLOW CYTOMETRY AND SINGLE CELL RNASEQ DATA, WE WILL IDENTIFY SPECIFIC SUPPRESSIVE IMMUNE CELL POPULATIONS AND RESISTANCE PHENOTYPES IN THE TME ASSOCIATED WITH DIFFERENT STK11-MLDD DIFFERENTIATION SUBSETS. AIM 2 CENTERS ON UNDERSTANDING TRAF2/CIAP1-MEDIATED IMMUNE EVASION AND VALIDATING TRAF2 AS A POTENTIAL CLINICAL TARGET IN LUNG CANCER. WE'LL CONDUCT EXPERIMENTS EVALUATING CHANGES IN TNF SIGNALING RESULTING FROM STK11 LOSS AND TRAF2/CIAP1, ASSESSING THEIR IMPACT ON ANTI-TUMOR IMMUNITY. ADDITIONALLY, WE WILL CONDUCT IN VIVO EXPERIMENTS TO EXAMINE STK11-/TRAF2-MEDIATED EFFECTS ON THE TME AND THE POTENTIAL FOR TRAF2 INHIBITION TO ENHANCE ICB RESPONSE. WE ANTICIPATE THAT OUR RESULTS WILL ESTABLISH TRAF2/CIAP1 INHIBITION AS A PROMISING CLINICAL TARGET FOR STK11- DEFICIENT LUNG CANCER, WHILE ALSO DEFINING NOVEL MECHANISMS OF IMMUNE RESISTANCE AND ADDITIONAL PRECISION TREATMENT CANDIDATES FOR THESE CANCERS. FURTHERMORE, THE STK11-MLDD BIOMARKER IS EXPECTED TO HAVE USE NOT ONLY AS A CLINICAL PREDICTOR OF ICB RESPONSE, BUT ALSO POTENTIALLY AS A 'TREATMENT-SELECTIVE' BIOMARKER THAT COULD BE USED TO IDENTIFY PATIENTS LIKELY TO RESPOND TO PRECISION APPROACHES SUCH AS CIAP1 INHIBITION. AS A PHYSICIAN-SCIENTIST IN THORACIC ONCOLOGY, MY CAREER GOAL IS TO BECOME A SUCCESSFUL INDEPENDENT ACADEMIC INVESTIGATOR, FOCUSING ON STK11-MUTATED NSCLC TO IMPROVE TREATMENTS AND OUTCOMES FOR PATIENTS WITH THESE CANCERS. WE HAVE OUTLINED A DETAILED MENTORSHIP AND CAREER DEVELOPMENT PLAN THAT WILL COMPLEMENT MY SCIENTIFIC APPROACHES AND PROMOTE MASTERY OF SKILLS NECESSARY FOR MY LONG-TERM SUCCESS, WITH SPECIFIC FOCUS IN THE AREAS OF 1) BIOINFORMATICS AND BIOSTATISTICS, 2) TUMOR IMMUNOLOGY AND IMMUNE ONCOLOGY, 3) ACADEMIC LEADERSHIP. ACHIEVING THESE GOALS WILL ACCELERATE MY SUCCESS AND MAXIMIZE MY LONG-TERM IMPACT IN THE FIELD.
$0 9/9/24 Not listed
BIOMARKER-DRIVEN STRATEGIES TO OVERCOME IMMUNOTHERAPY RESISTANCE IN STK11-DEFICIENT NSCLC - SUMMARY DESPITE SIGNIFICANT ADVANCES IN IMMUNO-ONCOLOGY (IO) TREATMENTS, LUNG CANCERS WITH LOSS-OF-FUNCTION MUTATIONS IN STK11, COMPRISING 20-30% OF CASES, DEMONSTRATE POOR PROGNOSIS DUE TO RESISTANCE TO THESE STRATEGIES. OUR PROPOSAL TARGETS THE INTERACTION BETWEEN SPECIFIC TUMOR 'DIFFERENTIATION PHENOTYPES' AND IMMUNE RESISTANCE PATHWAYS, ASSOCIATED WITH STK11-DEFICIENT LUNG CANCERS. FIRSTLY, WE'VE FOUND THAT THESE DIFFERENTIATION PHENOTYPES DRASTICALLY INFLUENCE THE IMMUNE COMPOSITION OF THE TUMOR MICROENVIRONMENT (TME) AND THE PATIENT'S RESPONSE TO IMMUNE CHECKPOINT BLOCKADE (ICB). FURTHERMORE, WE'VE DEVELOPED STK11-MLDD, A NOVEL BIOMARKER THAT MEASURES THESE DIFFERENTIATION PHENOTYPES AND MAY PREDICT ICB BENEFIT. SECONDLY, WE'VE IDENTIFIED THE IMMUNE REGULATOR TRAF2 AND ITS PARTNER CIAP1 AS PROMOTERS OF IMMUNE RESISTANCE, SPECIFICALLY IN THE CONTEXT OF STK11 DEFICIENCY, AND APPEAR TO BE LINKED TO THE NEUROENDOCRINE DIFFERENTIATION PHENOTYPE. THESE FINDINGS PROVIDE THE FOUNDATION FOR OUR TWO COMPLEMENTARY AIMS. AIM 1 FOCUSES ON CHARACTERIZING THE INTERACTION BETWEEN TUMOR DIFFERENTIATION PHENOTYPES, CORRESPONDING IMMUNE TME PHENOTYPES, AND CLINICAL RESPONSE TO ICB. WE'LL VALIDATE THE STK11-MLDD BIOMARKER IN MULTIPLE PATIENT COHORTS AND DEVELOP IT AS A CLINICAL TOOL FOR FUTURE TRIALS. ADDITIONALLY, USING FLOW CYTOMETRY AND SINGLE CELL RNASEQ DATA, WE WILL IDENTIFY SPECIFIC SUPPRESSIVE IMMUNE CELL POPULATIONS AND RESISTANCE PHENOTYPES IN THE TME ASSOCIATED WITH DIFFERENT STK11-MLDD DIFFERENTIATION SUBSETS. AIM 2 CENTERS ON UNDERSTANDING TRAF2/CIAP1-MEDIATED IMMUNE EVASION AND VALIDATING TRAF2 AS A POTENTIAL CLINICAL TARGET IN LUNG CANCER. WE'LL CONDUCT EXPERIMENTS EVALUATING CHANGES IN TNF SIGNALING RESULTING FROM STK11 LOSS AND TRAF2/CIAP1, ASSESSING THEIR IMPACT ON ANTI-TUMOR IMMUNITY. ADDITIONALLY, WE WILL CONDUCT IN VIVO EXPERIMENTS TO EXAMINE STK11-/TRAF2-MEDIATED EFFECTS ON THE TME AND THE POTENTIAL FOR TRAF2 INHIBITION TO ENHANCE ICB RESPONSE. WE ANTICIPATE THAT OUR RESULTS WILL ESTABLISH TRAF2/CIAP1 INHIBITION AS A PROMISING CLINICAL TARGET FOR STK11- DEFICIENT LUNG CANCER, WHILE ALSO DEFINING NOVEL MECHANISMS OF IMMUNE RESISTANCE AND ADDITIONAL PRECISION TREATMENT CANDIDATES FOR THESE CANCERS. FURTHERMORE, THE STK11-MLDD BIOMARKER IS EXPECTED TO HAVE USE NOT ONLY AS A CLINICAL PREDICTOR OF ICB RESPONSE, BUT ALSO POTENTIALLY AS A 'TREATMENT-SELECTIVE' BIOMARKER THAT COULD BE USED TO IDENTIFY PATIENTS LIKELY TO RESPOND TO PRECISION APPROACHES SUCH AS CIAP1 INHIBITION. AS A PHYSICIAN-SCIENTIST IN THORACIC ONCOLOGY, MY CAREER GOAL IS TO BECOME A SUCCESSFUL INDEPENDENT ACADEMIC INVESTIGATOR, FOCUSING ON STK11-MUTATED NSCLC TO IMPROVE TREATMENTS AND OUTCOMES FOR PATIENTS WITH THESE CANCERS. WE HAVE OUTLINED A DETAILED MENTORSHIP AND CAREER DEVELOPMENT PLAN THAT WILL COMPLEMENT MY SCIENTIFIC APPROACHES AND PROMOTE MASTERY OF SKILLS NECESSARY FOR MY LONG-TERM SUCCESS, WITH SPECIFIC FOCUS IN THE AREAS OF 1) BIOINFORMATICS AND BIOSTATISTICS, 2) TUMOR IMMUNOLOGY AND IMMUNE ONCOLOGY, 3) ACADEMIC LEADERSHIP. ACHIEVING THESE GOALS WILL ACCELERATE MY SUCCESS AND MAXIMIZE MY LONG-TERM IMPACT IN THE FIELD.
$281.4k 9/2/24