Area:
cancer biology, cancer genomics, target identification, rare disease
Website:
mackeiganlab.org
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High-probability grants
According to our matching algorithm, Jeffrey P MacKeigan is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2021 |
Mackeigan, Jeffrey Paul |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Evaluating a Novel Autophagy Inhibitor in Kras-Driven Lung Cancer @ Michigan State University
PROJECT SUMMARY Autophagy is an intracellular recycling process controlled by the kinase ULK1 that is important in the survival and growth of KRAS mutant lung tumors. Our team and others have shown that nutrient-stressed non-small cell lung cancer (NSCLC) cells are highly sensitive to ULK1 inhibition, which suggests that nutrient depletion caused by tumor growth may create vulnerability to autophagy inhibition. Because the field lacks potent and selective small-molecule inhibitors that target ULK1 in vivo, we have developed and published a potent and selective ULK1 inhibitor, ULK-101. In this application, we propose preclinical studies to further develop ULK-101 as an anti-cancer agent, and we will evaluate the compound both alone and in combination with molecularly-targeted therapies. We hypothesize that ULK-101 will suppress autophagy through ULK1 inhibition and thereby reduce KRAS-driven lung tumor growth and improve therapeutic efficacy. To test our hypothesis, we propose the following aims: Specific Aim #1: Determine the efficacy of a potent and selective ULK1 inhibitor on autophagy and tumor burden in mutant KRAS-driven NSCLC. In Aim 1, we will establish the level of autophagy inhibition by ULK- 101 in engrafted lung tumor cells. These KRASG12C lung cancer xenograft models will be used to test the hypothesis that ULK-101 treatment reduces tumor progression and that dual targeting of both KRAS and ULK1 will be an effective strategy for KRASG12C driven lung tumors. Specific Aim #2: Establish the therapeutic potential of an ULK1 inhibitor in genetically engineered NSCLC mouse models. In Aim 2, we will test whether the small molecule inhibitor ULK-101 will decrease tumor burden as a single agent in a KrasLSL-G12D and KrasLSL-G12C mouse models of NSCLC. Further, we expect that ULK-101 will enhance the sensitivity of tumors to clinically relevant therapies, including the first KRAS-targeted drug (AMG-510), to show promise in clinical trials of NSCLC. The mouse models used here complement the xenograft models by featuring mice with a functional immune system, tumors at the appropriate site, and disease progression that parallels the progression of human lung cancer. We will exploit a unique vulnerability in KRAS-driven tumors by inhibiting the autophagy pathway with a novel molecularly targeted therapy, ULK-101. While directly targeting KRAS has historically proven challenging, there has been a recent breakthrough with allele-specific inhibitors, prompted by promising early results in clinical trials with AMG-510, a G12C-specific KRAS inhibitor. Ultimately, we hope that evaluating ULK-101 as a single agent and in combination with other therapeutics like AMG-510, will provide essential data to serve as a foundation for new and more effective treatments for lung cancer patients.
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1 |
2021 |
Mackeigan, Jeffrey Paul |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Therapeutic Potential of Targeting Dna Repair Deficiency in Tsc @ Michigan State University
PROJECT SUMMARY/ ABSTRACT Using next-generation sequencing, researchers have identified somatic mutations as essential for tumor etiology and evolution. We now know that many cancers also have a substantial germline component. Germline mutations increase the lifetime risk of cancer and often result in earlier onset and more advanced disease. A significant portion of germline cancer mutations occur in DNA damage response (DDR) genes, which lead to the failed repair of DNA lesions, the accumulation of somatic mutations and structural variants that promote oncogenesis. In our recent genomic analysis of tuberous sclerosis (TSC) patients, we unexpectedly found that double-strand break (DSB) repair deficiencies are frequent in the germline. TSC is a tumor syndrome characterized by mutations in the tumor suppressors, TSC1 and TSC2, causing dysregulated activation of the mTOR pathway. Breast, ovarian, and metastatic prostate cancers also harbor pathogenic germline mutations in DDR repair genes and somatic mutations leading to hyperactive mTOR signaling. As such, we aim to evaluate the therapeutic activity of DDR-targeted agents alone and in combination with mTOR inhibitors for reduced tumor burden in TSC, which may also provide valuable insights for cancers characterized by hyperactive mTOR signaling. Our central hypothesis is that a defective DNA damage response cooperates with mTOR pathway activation to drive tumor growth. We will use genome editing tools to introduce specific DSB repair variants into isogenic cell lines and then measure DNA damage and mTOR signaling. We will assay cell viability and anchorage- independent growth to determine if DSB mutations promote clonogenic potential and survival in isogenic cells. Further, in Specific Aim 2, we plan to explore therapeutic potential using targeted agents to DDR alone and in combination with mTOR inhibitors in vivo. Specifically, we will use syngeneic mouse models to evaluate the efficacy of CHK inhibitors or PARP inhibitors as single agents and in combined dosing strategies with everolimus. Through the proposed research, we will determine whether germline DSB repair defects create a unique therapeutic opportunity in mTOR-driven tumors. Our results could have broad-reaching implications given the essential roles of germline DDR mutations and somatic mTOR pathway mutations in tumor formation and malignant lesions.
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1 |