Phase I Amount
$1,160,011
Compelling evidence suggests that careful and therapeutically relevant activation of the STING (STimulator of INterferon Genes) pathway is necessary to elicit potent anti-cancer innate immune responses. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the STING pathway's only known direct negative regulator expressed in many tumor types, and, when it is overexpressed, tumors show limited efficacy to front-line therapies. Such as, in triple-negative breast cancer (TNBC), high ENPP1 expression is associated with drug resistance and poor prognosis. If a safe and efficacious ENPP1 inhibitor were available, it would have widespread utility for multiple cancer types and, if used in combination with other cancer therapies, may enhance their performance. Towards this end, we have developed an orally bioavailable potent small-molecule inhibitor of ENPP1 called SR-8541A. It inhibits hENPP1 activity with an IC50 of 3.6 nM (Ki=1.9 nM) and demonstrates robust selectivity. We have established that it activates the STING pathway, promotes immune cell infiltration, and inhibits cancer spheroid growth. Furthermore, in syngeneic tumor mouse models, SR-8541A demonstrates a synergistic effect with radiation, and a preliminary study also shows synergy with checkpoint inhibitors. To date, we have completed preclinical development activities on SR-8541A that include API development and manufacturing, stability, pharmacokinetics, tolerability, and preliminary toxicology (mouse, rat, dog). The overall goal of this Direct to Phase II SBIR application is to complete non-GLP and GLP preclinical studies for our lead molecule SR-8541A with TNBC as our initial focus. In Aim 1, we will evaluate the efficacy of SR-8541A in combination with FDA-approved drug regimens (e.g., cisplatin, anti-mCTLA-4, anti-mPD-1, PARP inhibitor) in 4T-1 and EMT-6 breast cancer mouse models. In Aim 2, we will conduct IND enabling GLP toxicology study in dogs as the rat GLP study is complete. In Aim 3, we will develop and manufacture cGMP clinical-grade tablets necessary to conduct a Phase 1 clinical trial. Direct to Phase II SBIR success will result in the completion of the required preclinical studies to seek IND acceptance for a first-in-human Phase I clinical trial and to engage with private-sector investors in funding clinical trials in TNBC. If SR-8541A is approved for patient use, it would be the first-in-class molecule to modulate the innate immune system, expanding the benefits of immunotherapy to more patients.
Public Health Relevance Statement: PROJECT NARRATIVE Current immunotherapies activate only the adaptive immune system and prove ineffective when cancer silences the innate immune response, the other central arm of immunity. Stingray Therapeutics has developed a novel potent small-molecule inhibitor of ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase family member 1), a dual checkpoint regulator of innate and adaptive immune responses that alone or in combination with immune checkpoint inhibitors or standard of care treatments may produce superior outcomes in patients with high ENPP1-expressing tumors, such as triple-negative breast cancer. This Direct to Phase II SBIR application aims to complete non-GLP and GLP preclinical studies on our lead ENPP1 inhibitor SR-8541A necessary to seek IND acceptance for a first-in-human Phase I clinical trial.
Project Terms: Adenosine; inhibitor; Breast; malignant breast neoplasm; Breast Cancer; malignant breast tumor; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; cell motility; Cell Locomotion; Cell Migration; Cell Movement; Cellular Migration; Cellular Motility; Motility; Cells; Cell Body; Cisplatin; CDDP; Cis-diammine-dichloroplatinum; Cis-diamminedichloridoplatinum; Cis-diamminedichloro Platinum (II); Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cisplatina; Cisplatinum; Cysplatyna; Dichlorodiammineplatinum; Peyrone's Chloride; Peyrone's Salt; Platinum Diamminodichloride; cis dichlorodiammineplatinum; cis platinum compound; cis-Diaminedichloroplatinum; cis-Diamminedichloroplatinum; cis-Diamminedichloroplatinum(II); cis-Dichlorodiammineplatinum(II); cis-Platinum; Clinical Trials; Cytosol; DNA; Deoxyribonucleic Acid; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enzymes; Enzyme Gene; Gene Expression; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Half-Life; Human; Modern Man; Immunity; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; 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; In Vitro; Laboratories; Lead; Pb element; heavy metal Pb; heavy metal lead; Mus; Mice; Mice Mammals; Murine; Metastasis; Metastasize; Metastatic Lesion; Metastatic Mass; Metastatic Neoplasm; Metastatic Tumor; Secondary Neoplasm; Secondary Tumor; cancer metastasis; tumor cell metastasis; Neoplasm Metastasis; Patients; Pharmacokinetics; Drug Kinetics; Pharmacology; Phosphodiesterases; phosphoric diester hydrolase; Private Sector; Proteins; pyrophosphatase; Common Rat Strains; Rat; Rats Mammals; Rattus; Development and Research; R & D; R&D; research and development; Safety; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; Tablets; Testing; Tissues; Body Tissues; Toxicology; Work; plasma cell membrane glycoprotein PC-1; ENPP1 protein; PC-1 glycoprotein; ecto-nucleotide pyrophosphatase phosphodiesterase 1; ectonucleotide pyrophosphatase phosphodiesterase 1; nucleotide pyrophosphatase-alkaline phosphodiesterase I; Family member; base; dosage; Site; Surface; Clinical; Phase; Funding; Oncology Cancer; Oncology; Immunological response; host response; immune system response; immunoresponse; Immune response; Therapeutic; stingray; Infiltration; Malignant Cell; cancer cell; Rivers; programs; Immunes; Immune; Oral; extracellular; Performance; success; Intercept; synergism; novel; Position; Positioning Attribute; Radiation; Modeling; Phase I Clinical Trials; Early-Stage Clinical Trials; Phase 1 Clinical Trials; phase I protocol; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; preventing; prevent; 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; CTLA4 gene; PD 1; PD-1; PD1; programmed cell death 1; programmed death 1; sle2; systemic lupus erythematosus susceptibility 2; programmed cell death protein 1; Breast tumor model; mammary cancer model; mammary tumor model; Breast Cancer Model; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Development; developmental; Pathway interactions; pathway; preclinical study; pre-clinical study; triple-negative invasive breast carcinoma; TNBC; triple-negative breast cancer; tumor microenvironment; cancer microenvironment; data modeling; model of data; model the data; modeling of the data; efficacy evaluation; efficacy analysis; efficacy assessment; efficacy examination; evaluate efficacy; examine efficacy; Outcome; cancer type; pre-clinical research; preclinical research; chemotherapy; mouse model; murine model; tumor; overexpression; overexpress; FDA approved; standard of care; preclinical evaluation; pre-clinical evaluation; Regimen; arm; The Cancer Genome Atlas; TCGA; small molecule inhibitor; inflammatory milieu; inflammatory environment; adaptive immune response; Innate Immune System; Adaptive Immune System; acquired immune system; Innate Immune Response; preclinical development; pre-clinical development; Immune checkpoint inhibitor; Checkpoint inhibitor; immune check point inhibitor; Stimulator of Interferon Genes; cGAMP STING; cGAMP-STING; cGAMP/STING; cGAS/STING; first-in-human; first in man; anti-cancer; anticancer; side effect; pharmacokinetics and pharmacodynamics; PK/PD; STING agonists; Prognosis
