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Co-Targeting PARP and PI3K To Enhance Immune-Responsiveness in Prostate Cancer

Inventor(s):

    SUMMARY

    • Metastatic castration-resistant prostate cancer(mCPRC) burdens patients with an unfavorable prognosis and an impaired quality of life.  PTEN Loss-of-Function (LOF) suppresses tumor cell-intrinsic interferon gene stimulator (STING) expression, inhibits downstream signaling, and contributes to immune checkpoint blockade (ICB) resistance in over 50% or mCPRCs.
    • Only 10% of mCRPC patients respond to CTLA4 and PD1 pathway-directed therapy. To increase this percentage, researchers study fundamental DNA repair and oncogenic signaling pathways.
    • The inventors have developed a novel PARPi/PI3Ki combination therapy modeled on PTEN deficiency which activates the c-GAS/STING pathway within tumor-associated macrophages.  Their therapy enhances T cell recruitment and activation in c-Myc-driven murine prostate cancer models.
    • In vivo proof-of-concept experiments with PARPi/PI3Ki combination therapy caused murine tumor regression.  Flow cytometric analyses confirmed increased infiltration of activated macrophages and reduced gene expression associated with pathogenic fibroblast signaling pathways.

     

    FIGURE

    A)  Inventors at the University of Chicago propose treating mCPRC by activating the myeloid cell c-GAS-STING pathway with PARPi/PI3Ki combination therapy or STING agonists within the tumor microenvironment. The combination of PARPi + PI3Ki induces the release of double-stranded DNA (dsDNA) fragments into microvesicles that activate the c-GAS/STING pathway within myeloid cells. As STING pathway activation induced by DNA damaging agents is abolished within the tumor microenvironment of PTEN-deficient PC, the inventors propose DNA damage-mediated STING activation to enhance immune responsiveness in prostate cancer.
    B)  PARPi/PI3Ki/ADT Induces Tumor Regression in Myc-CAP via a Non-Tumor Cell Autonomous. Immune Mechanism. Syngeneic PTEN-proficient MyC-CaP tumor-bearing immuno-competent FVB and immuno-deficient mice were treated with drugs indicated under un-castrated or castrated conditions, and in the presence or absence of PDL1 antibody. Measurements were collected until volume reached 2000-2500 mm3. For all groups, n=3-5 mice.

    ADVANTAGES

    ADVANTAGES

    • DNA damage elicited by PARPi/PI3Ki reprogramming the myeloid tumor microenvironment to enhance anti-tumor immunity

    • Enhanced T cell infiltration resulting in tumor regression

    • Relief of immune suppression

    APPLICATIONS

    • Cancer immunotherapy
    • Patient stratification
    • In vivo proof of concept with murine tumors.
    • Preliminary immunotherapy profiling of patients in Rucaparib/Nivolumab clinical trial.

    TECH DETAILS

    Published
    7/26/2022

    Reference ID
    19-T-128

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