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Principal Investigator: PAUL B FISHER
Organization: VIRGINIA COMMONWEALTH UNIVERSITY
Fiscal Year: 2024
Award: $447,407
Funding agency: National Cancer Institute
Prostate cancer (CaP) is the most commonly diagnosed cancer and the second leading cause of cancer
death in men over the age of fifty. Bone is the primary site of metastasis in patients whose CaP progresses
beyond organ confinement. The absence of curative therapies for metastatic CaP emphasizes the imperative to
develop innovative technologies for target-specific delivery of therapeutic agents as well as novel treatment
strategies that are efficacious with minimal toxicity. Our investigative team seeks to address different aspects of
CaP bone metastasis through a highly integrated and focused research effort that will enhance our
comprehension of the mechanisms underlying CaP progression and improve therapeutic strategies to eradicate
bone metastases and prevent relapse. Our early work using a subtraction hybridization screen identified two
unique genes, i.e., melanoma differentiation associated gene-9 (mda-9) and mda-7/IL-24 from terminally
differentiating human melanoma cells. Subsequent research established MDA-9 as a key promoter of cancer
invasion and metastasis, whereas MDA-7/IL-24 was recognized as a broad-spectrum anti-cancer therapeutic.
Using a newly developed syngeneic pre-clinical model of CaP bone metastasis, we will investigate the interplay
between CaP bone metastases and the bone niche orchestrated by MDA-9 and evaluate therapeutic activity of
‘first-in-class’ small molecule inhibitor of MDA-9 (i.e., PDZ1i) for targeting both metastatic CaP cells and the bone
niche. By exploiting the exquisite ability and high efficiency of T cells to locate and destroy disseminated cancer
cells, especially those in normally inaccessible sites, i.e., bone, we will engineer CaP-reactive T cells to produce
MDA-7/IL-24, a unique cancer-selective apoptosis-inducing cytokine, for improved capacity to attack potentially
antigenically heterogenous bone metastases. Last, based on the ability of PDZ1i to reprogram the immune niche
in the tumor microenvironment, we will combine engineered T cells producing next-generation MDA-7/IL-24
(“Superkine MDA-7/IL-24“, “S7M”), having enhanced secretion and stability, with MDA-9-targeted therapy for
synergistic elimination of CaP bone lesions. We anticipate that the insights garnered from these studies will
enable a more precise molecular understanding of bone metastasis development for target discovery, rational
design of improved cellular immunotherapy, and combinatorial treatment modalities optimized to achieve a
maximum therapeutic potential. Successful completion of this multidisciplinary, synergistic research program will
provide a rapid path to translate these technologies and strategies into the clinic to safely and effectively manage
this most common skeletal complication of CaP.
Terms: <Address><Adherence><Age><Androgenic Agents><Androgenic Compounds><Androgens><Animal Model><Animal Models and Related Studies><Anti-Angiogenesis><Antiangiogenesis><Antigens><Autophagocytosis><Bone Cancer><Bone Marrow Blood-Deriving Cell><Bone Marrow Blood-Forming Cell><Bone Marrow Cells><Bone Metastasis><Bone cancer metastatic><Bony metastasis><Cancer Cause><Cancer Etiology><Cancer Induction><Cancers><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cellular immunotherapy><Cessation of life><Clinic><Clinical><Complication><Comprehension><Data><Death><Development><Diagnosis><Disease><Disorder><Endocrine Gland Secretion><Engineering><Environment><Genes><Goals><Hormones><Human><IGF-Binding Proteins><IGFBP><IL-24 protein><IL10B><IL24><IL24 gene><Immune><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapeutic agent><Immunotherapy><Induction of Apoptosis><Insulin-Like Growth-Factor-Binding Proteins><Interleukin-24><Intracellular Communication and Signaling><Invaded><Lesion><MDA-9><MDA7><MDA7 Protein><Malignant Bone Neoplasm><Malignant Cell><Malignant Melanoma><Malignant Neoplasms><Malignant Osseous Neoplasm><Malignant Osseous Tumor><Malignant Tumor><Malignant Tumor of the Bone><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Melanoma><Melanoma Cell><Melanoma Differentiation Associated Protein 7><Melanoma differentiation associated gene - 7><Melanoma differentiation associated gene-9><Metastasis><Metastasis to bone><Metastasize><Metastatic Cancer to the Bone><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Bone><Metastatic Prostate Cancer><Metastatic Tumor><Metastatic Tumor to the Bone><Metastatic malignant neoplasm to bone><Mob-5><Modality><Modeling><Modern Man><Molecular><Molecular Target><Morbidity><Morbidity - disease rate><Neoplasm Metastasis><Organ><Osseous Cancer><Osseous metastasis><Pathogenicity><Patients><Phenotype><Position><Positioning Attribute><Pre-Clinical Model><Preclinical Models><Procedures><Process><Property><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate Carcinoma Metastatic><Prostate malignancy><Prostatic Cancer><Proteins><Reagent><Receptor Protein><Research><Research Proposals><Role><SDCBP><ST16><ST16 Protein><STAT3><STAT3 gene><Scheme><Secondary Neoplasm><Secondary Tumor><Secondary cancer of bone><Secondary malignancy of bone><Secondary malignant neoplasm of bone><Signal Transduction><Signal Transduction Systems><Signaling><Site><Skeletal metastasis><Solid><Somatomedin-Binding Proteins><Suppression of Tumorigenicity 16 Protein><T Cell Specificity><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T-Cell Immunologic Specificity><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><Technology><Testing><Therapeutic><Therapeutic Agents><Therapeutic Androgen><Therapeutic Hormone><Toxic effect><Toxicities><Translating><Tumor Cell><Tumor Immunity><Up-Regulation><Upregulation><Work><adoptive T cell transfer><adoptive T-cell therapy><advanced prostate cancer><ages><angiogenesis><anti-angiogenesis therapy><anti-cancer><anti-cancer research><anti-cancer therapeutic><anti-tumor immunity><antiangiogenesis therapy><anticancer activity><antitumor immunity><autophagy><biological signal transduction><bone><bone neoplasm secondary><cancer cell><cancer diagnosis><cancer immunity><cancer metastasis><cancer microenvironment><cancer research><carcinogenesis><cell-based immunotherapy><check point blockade><checkpoint blockade><combinatorial><conventional therapy><conventional treatment><curative intervention><curative therapeutic><curative therapy><curative treatments><cytokine><determine efficacy><developmental><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><engineered T cells><evaluate efficacy><examine efficacy><genetically engineered T-cells><immune cell therapy><immune check point blockade><immune checkpoint blockade><immune drugs><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunotherapeutics><immunotherapy agent><improved><inhibitor><innovative technologies><insight><insulinlike growth factor binding protein><male><malignancy><mda-7 gene product><mda-7 protein><men><metastatic process><model of animal><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mortality><mouse model><multidisciplinary><murine model><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pharmacologic><pre-clinical><preclinical><prevent relapse><programs><promoter><promotor><prostate cancer cell><prostate cancer metastasis><prostate cancer model><prostate cancer progression><prostate cancer treatment><prostate tumor cell><prostate tumor model><rational design><receptor><relapse prevention><skeletal><small molecular inhibitor><small molecule><small molecule inhibitor><social role><subtraction hybridization><success><syndecan binding protein><synergism><syntenin><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic T-cell platform><therapeutic target><thymus derived lymphocyte><transgenic T- cells><treatment strategy><tumor><tumor cell metastasis><tumor microenvironment>