The majority of cancer deaths are caused by dissemination and growth of secondary tumors throughout the body. While the 5-year survival rate for localized cancers has dramatically improved over the last four decades of drug development, the survival rates for cancer patients with advanced or metastatic disease remains abysmal, with median survival of Stage 4 patients at 10 months following diagnosis. Patients diagnosed with advanced or metastatic cancers are furthermore considered terminal as metastatic lesions are resistant to current therapeutic options. New therapeutic agents that can effectively treat and enforce regression of advanced cancers or established metastases are urgently needed in the therapeutic repertoire, yet only immune checkpoint blockade therapies have shown the ability to prolong survival in a small subset of patients with Stage 4 cancer. Therefore, immunotherapies with novel mechanisms of action and complementarity to current therapies are urgently needed to increase the percentage of responding patients and improve cancer survival metrics in the United States. Our academic collaborators as well as other leading academic laboratories have identified an immunosuppressive signaling pathway driven by two complementary enzymes that is critical to the progression of solid tumors by generating an immunosuppressive tumor microenvironment. Both our discovery work and recently published studies demonstrate this pathway is a critical node in the progression of multiple cancer types such as sarcoma, melanoma and breast cancer, yet prior commercial and academic attempts to drug this pathway have failed due to lack of potency, specificity and/or poor pharmacological properties. We are the first group to have developed lead compounds against this pathway that show exceptional potency and specificity while avoiding the pharmacologic liabilities of other drug development programs. Importantly, our therapies show promise in treating advanced and metastatic cancers and are characterized by low nanomolar potency (<50 nM, a 100-fold improvement over published molecules), no off-target activity, high metabolic stability, excellent oral pharmacokinetic properties and promising in vivo toxicology. Here we propose to nominate a development candidate through pharmacodynamic assays, dose-range finding studies and immunocompetent cancer models. The results of this research proposal will advance a first-in-class therapy toward clinical testing with the aim of curing patients who were once diagnosed as incurable. Specifically, the efficacy and preclinical data obtained from this application will support Phase 2 SBIR studies leading to an IND application.
Public Health Relevance Statement: Project narrative: This project advances a novel immunotherapy with both potent single agent activity and exceptional combinatorial activity that has the potential to enforce durable remissions in patients with advanced or metastatic solid cancers. Kayothera has developed this first-in-class therapy using a next-generation drug discovery platform in order to target an immunosuppressive signaling pathway critical to the survival of solid cancers. Specific aims outlined in the grant will provide the basis for advancing this therapy to IND-enabling experiments through a series of pharmacokinetic and pharmacodynamic assays.
Project Terms: Achievement Attainment; Achievement; inhibitor; Antibodies; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; malignant breast neoplasm; Breast Cancer; malignant breast tumor; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cause of Death; Cells; Cell Body; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Clinical Trials; Dendritic Cells; Veiled Cells; Diagnosis; Disease; Disorder; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Down-Regulation; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enzymes; Enzyme Gene; Exhibits; Freedom; Liberty; Grant; Growth; Generalized Growth; Tissue Growth; ontogeny; Half-Life; Human; Modern Man; Immune system; Immunologic Surveillance; Immune Surveillance; Immunologic Surveillances; Immunological Surveillance; Immunological Surveillances; Immunosurveillance; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; immunosuppressive response; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; Laboratories; Lead; Pb element; heavy metal Pb; heavy metal lead; Ligands; Macrophage; MÏ; melanoma; Malignant Melanoma; Methods; Monkeys; monocyte; Blood monocyte; Marrow monocyte; Mus; Mice; Mice Mammals; Murine; Neoplasm Metastasis; Metastasis; Metastasize; Metastatic Lesion; Metastatic Mass; Metastatic Neoplasm; Metastatic Tumor; Secondary Neoplasm; Secondary Tumor; cancer metastasis; tumor cell metastasis; Legal patent; Patents; Patients; Drug Kinetics; Pharmacokinetics; Program Development; Publishing; Rattus; Common Rat Strains; Rat; Rats Mammals; Research; Research Proposals; Retinoids; Retinoic Acid Agent; Retinoic Acid and Derivatives; Messenger RNA; mRNA; Signal Pathway; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Specificity; Survival Rate; Regulatory T-Lymphocyte; Treg; regulatory T-cells; Testing; Toxicology; Tretinoin; ATRA; Retinoic Acid; Trans Vitamin A Acid; Tretinoinum; Vitamin A Acid; all-trans-Retinoic Acid; all-trans-Vitamin A acid; trans-Retinoic Acid; United States; Work; Generations; Family member; Schedule; New Drug Approvals; improved; Hepatic; Solid; Phase; biologic; Biological; Series; Antigen Presentation; Nuclear Receptors; CD8 Cell; CD8 T cells; CD8 lymphocyte; CD8+ T cell; CD8+ T-Lymphocyte; CD8-Positive Lymphocytes; T8 Cells; T8 Lymphocytes; CD8-Positive T-Lymphocytes; anti-cancer immunotherapy; anticancer immunotherapy; immune-based cancer therapies; immunotherapy for cancer; immunotherapy of cancer; cancer immunotherapy; Solid Tumor; Solid Neoplasm; Intellectual Property; Critical Paths; Critical Pathways; Therapeutic; Therapeutic Agents; Metabolic; Genetic; Infiltration; tool; scaffold; scaffolding; Disseminated Malignant Neoplasm; Metastatic Cancer; Metastatic Malignant Neoplasm; Immune; Immunes; Oral; Tumor Tissue; Disease remission; Remission; neoplastic cell; Tumor Cell; Protein Isoforms; Isoforms; In complete remission; complete response; Primary Neoplasm; Primary Tumor; Structure; immunoregulation; Immunomodulation; immune modulation; immune regulation; immunologic reactivity control; immunomodulatory; immunoregulatory; novel; Cancer Remission; Localized Malignant Neoplasm; Local Cancer; Localized Cancer; Localized Malignancy; Pharmacodynamics; Modeling; Property; cross reactivity; drug development; Advanced Malignant Neoplasm; Advanced Cancer; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; drug discovery; Malignant Soft Tissue Neoplasm; malignant soft tissue tumor; sarcoma; CTLA4 gene; CD152; CD152 Antigen; CD152 Gene; CTLA 4; CTLA-4 Gene; CTLA4; CTLA4-TM; Cytotoxic T-Lymphocyte Protein 4; Cytotoxic T-Lymphocyte-Associated Antigen 4; Cytotoxic T-Lymphocyte-Associated Protein 4; Cytotoxic T-Lymphocyte-Associated Serine Esterase-4; cytotoxic T-lymphocyte antigen 4; ITGAX gene; CD11c; ITGAX; ITGAM gene; CD11b; CR3A; ITGAM; MAC1A; MO1A; Dose; Data; Immunocompetent; immune competent; Resolution; resolutions; in vivo; Cancer Model; CancerModel; Cancer Patient; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Development; developmental; Pathway interactions; pathway; pre-clinical; preclinical; next generation; cancer type; innovate; innovative; innovation; resistant; Resistance; combinatorial; clinical applicability; clinical application; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; tumor; oral immunotherapy; pharmacodynamic marker; pharmacodynamic biomarker; response markers; response biomarker; identification of biomarkers; marker identification; biomarker identification; nano-molar; nanomolar; patient subgroups; patient subpopulations; patient subtypes; patient subsets; cancer survival; experiment; experimental research; experiments; experimental study; immune check point; immunecheckpoint; immune checkpoint; check point blockade; checkpoint blockade; immune check point blockade; immune checkpoint blockade; PD-1 antibody therapy; PD-1 therapy; PD1 antibody therapy; PD1 based treatment; aPD-1 therapy; aPD-1 treatment; aPD1 therapy; aPD1 treatment; anti-PD-1 therapy; anti-PD-1 treatment; anti-PD1 treatment; anti-programmed cell death 1 therapy; anti-programmed cell death protein 1 therapy; programmed cell death protein 1 therapy; anti-PD1 therapy; immune cell infiltration of tumors; immune cells infiltrating the tumor; immune cells that infiltrate the tumor; infiltration of tumors by immune cells; intratumoral immune cell; intratumoral immune infiltrate; tumor immune cell; tumor immune infiltrate; tumor infiltration of immune cells; Tumor-infiltrating immune cells; aPD-1; aPD1; anti programmed cell death 1; anti-PD1; anti-programmed cell death protein 1; antiPD-1; antiPD1; aPD-1; aPD1; anti-PD-1; lead candidate; PK/PD; pharmacokinetics and pharmacodynamics; immune microenvironment; immunosuppressive microenvironment; immunosuppressive tumor microenvironment; tumor immune microenvironment; tumor-immune system interactions; antagonist; antagonism; pharmacologic
