SBIR-STTR Award

This proposal advances the development of a novel therapeutic for p53 wild type sarcomas. Our team has identified a novel MDM2 inhibitor, SA53, with best-in-class potency, bioavailability and in vivo efficacy across a broad range of preclinical models. It has also undergone extensive safety and pharmacokinetic testing, suitable for support of an IND submission, with an identified starting dose in humans. SA53 has the potential to facilitate apoptosis in p53 wild-type cancers and to spare normal tissue. To drive proof of concept, we will conduct a first in human trial to 1) identify a safe dose for future clinical trials, 2) establish the pharmacokinetic profile and appropriate safety endpoints, 3) in an expansion cohort, establish feasibility and early indication of efficacy in treating p53 wild type soft tissue sarcoma. Our primary objective is to rapidly and efficiently advance SA53 through clinical trials to implement a novel and innovative treatment for p53 wild type soft tissue sarcoma. Our approach is first establishing the recommended phase 2 dose in a trial for p53 wild type refractory solid tumors, then to apply this novel therapy in an expansion cohort targeting a pre-surgical window in soft tissue sarcoma patients. To achieve these goals, we will complete the following specific aims: Aim 1: We will complete GMP manufacturing of the drug and formulated clinical product suitable to complete a phase 1 clinical trial. Aim 2: We will conduct a phase 1 clinical trial to establish the recommended dose for phase 2 and early indication of feasibility and efficacy in soft tissue sarcoma patients. At the completion of this proposal, we will have completed a phase 1 trial to have established safety and preliminary efficacy, which will serve as the foundation for registration directed studies. In light of our exceptional in vivo efficacy data, we further believe that this can be a breakthrough paradigm-changing therapy for cancer treatment.

Public Health Relevance Statement:
Project narrative Sarcomas account for 13,000 new diagnoses per year in the United States. They are treated with major surgery, toxic chemotherapy, and/or radiation, but many fail therapy. More effective and less toxic therapies are needed. We propose development of a new drug that activates an intrinsic defense mechanism (p53). The target of our novel therapy is MDM2, which inactivates p53, thereby increasing treatment resistance. Other cancers have a similar mechanism for p53 inactivation thus, an effective new drug for relatively rare sarcomas may impact treatment paradigms for many other cancers as well.

Project Terms:
Abdominal; Abdomen; inhibitor; Biological Availability; Bioavailability; Physiologic Availability; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell Death; necrocytosis; cell growth; Cellular Expansion; Cellular Growth; Clinical Trials; Defense Mechanisms; psychological defense mechanism; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Foundations; Future; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Half-Life; Human; Modern Man; Light; Photoradiation; liposarcoma; Monkeys; Patients; Drug Kinetics; Pharmacokinetics; Proteins; Rattus; Common Rat Strains; Rat; Rats Mammals; Recommendation; Recurrence; Recurrent; Safety; Testing; Thrombocytopenia; Thrombopenia; Toxicology; Treatment Protocols; Treatment Regimen; Treatment Schedule; United States; Work; TP53 gene; Antioncogene Protein p53; Cellular Tumor Antigen P53; Oncoprotein p53; P53; Phosphoprotein P53; Phosphoprotein pp53; Protein TP53; TP53; TRP53; Tumor Protein p53; Tumor Protein p53 Gene; p53 Antigen; p53 Genes; p53 Tumor Suppressor; protein p53; Apoptosis Pathway; Programmed Cell Death; Apoptosis; Clinical; Refractory; Phase; Funding; Solid Tumor; Solid Neoplasm; Desmoplastic Small Round-Cell Neoplasm; Desmoplastic Small Round Cell Tumor; Collaborations; Therapeutic; Normal tissue morphology; Normal Tissue; Area Under Curve; programs; Clinic; Operative Surgical Procedures; Operative Procedures; Surgical; Surgical Interventions; Surgical Procedure; surgery; experience; neoplastic cell; Tumor Cell; Tumor Suppressor Proteins; tumor suppressor; tumor growth; tumor initiation; cohort; Toxic effect; Toxicities; Adjuvant Therapy; adjuvant treatment; Primary Neoplasm; Primary Tumor; novel; drug metabolism; Positioning Attribute; Position; 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; HDM2; MDM2; MDMX protein; Mdm-2 protein; Oncoprotein MDM2; mdm-2 oncogene protein; mdm2 protein; p53-Binding Protein MDM2; MDM2 gene; Malignant Soft Tissue Neoplasm; malignant soft tissue tumor; sarcoma; preventing; prevent; small molecule; Dose; Data; High Prevalence; Mutate; Pre-Clinical Model; Preclinical Models; in vivo; Newly Diagnosed; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Molecular; Development; developmental; therapy resistant; resistance to therapy; resistant to therapy; therapeutic resistance; treatment resistance; burden of disease; disease burden; years of life lost to disability; years of life lost to disease; burden of illness; Advanced Development; cancer type; innovate; innovative; innovation; 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; differentiation factors; morphogenic factors; morphogens; tumor; arm; screenings; screening; phase 1 trial; phase I trial; Soft tissue sarcoma; efficacy study; clinical development; cancers that are rare; rare malignancy; rare tumor; rare cancer; first in man; first-in-human; early phase trial; Chemotherapy and Radiation; chemo/radiation therapy; chemotherapy and radiotherapy; radiation or chemotherapy; Chemotherapy and/or radiation; manufacture