SBIR-STTR Award

There is an urgent need for novel therapies to treat malignant astrocytomas, the most common and aggressive primary tumor of the nervous system. Using current standard of care, patients diagnosed with these tumors have an average life expectancy of 18 months and there is no effective treatment available. The laboratory of Dr. Nephi Stella recently discovered a new subclass of indole compounds that activate GPR124, a GPCR with established relevance in tumor pathogenesis. These indoles demonstrate efficacy in both in vitro and in vivo rodent models of malignant astrocytomas. Notably, the therapeutic effective doses of indoles do not produce overt toxicity in mice. The goal of Stella Therapeutics is to develop drugs that target GPR124 and efficiently treat malignant astrocytomas with minimal side-effects. In this proof-of-concept work, we will: Aim 1: Validate an in vitro assay tha measures the potency of GPR124 agonists in human astrocytoma cells. Use this assay to screen 40 analogues of NMP-192 (EC50 = 54 nM). Aim 2: Select the 2 most promising compounds and establish their pharmacokinetic and acute toxicity profiles in mice, as well as measure their in vivo efficacy in a xenograft mouse model of malignant astrocytomas. By the end of this Phase I SBIR, Stella Therapeutics will have developed a lead compound that activates GPR124, exhibits in vivo efficacy and induces minimal side effects. The resulting phase II SBIR will further optimize the drug-like properties of the lead compound by using state-of-the-art medicinal chemistry and chemo-informatics. We will systematically measures their therapeutic efficacy and side effects to establish a therapeutic index. Stella Therapeutics is dedicated to developing and patenting novel drug-based therapies to treat malignant tumors.

Public Health Relevance:
There is an urgent need for novel therapies to treat malignant astrocytomas, the most common and aggressive primary tumor of the nervous system. This phase I SBIR outlines a strategy to develop a new therapeutic approach to treat these tumors. By combining the strength of several state-of-the-art approaches in drugs development, we will develop small molecules that activate a novel therapeutic target expressed by malignant astrocytomas. Stella Therapeutics is dedicated to developing and patenting novel drug-based therapies to treat malignant tumors.

Public Health Relevance Statement:
There is an urgent need for novel therapies to treat malignant astrocytomas, the most common and aggressive primary tumor of the nervous system. This phase I SBIR outlines a strategy to develop a new therapeutic approach to treat these tumors. By combining the strength of several state-of-the-art approaches in drugs development, we will develop small molecules that activate a novel therapeutic target expressed by malignant astrocytomas. Stella Therapeutics is dedicated to developing and patenting novel drug-based therapies to treat malignant tumors.

Project Terms:
Acute; Adverse effects; Agonist; analog; Anaplastic astrocytoma; Animals; Apoptosis; Astrocytoma; base; Biological; Biological Assay; Brain Neoplasms; cancer cell; Cardiac; Cell Line; Cell Survival; Cells; Commit; Diagnosis; Dose; Drug Delivery Systems; drug development; Drug Formulations; Drug Kinetics; effective therapy; Exhibits; G-Protein-Coupled Receptors; Generations; Glioblastoma; Glioma; Goals; Growth; Hepatic; Human; In Vitro; in vitro Assay; in vivo; Indoles; Informatics; Injection of therapeutic agent; injured; innovation; Killings; Laboratories; Lead; Legal patent; Life Expectancy; Malignant Neoplasms; Measures; Metabolism; Modeling; mouse model; Mus; Nervous system structure; Neurons; new therapeutic target; novel; novel therapeutic intervention; Pathogenesis; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; pharmacophore; Phase; pre-clinical; Primary Neoplasm; Property; Reporter; Rodent Model; scaffold; Screening procedure; Small Business Innovation Research Grant; small molecule; standard of care; Stem cells; Structure-Activity Relationship; System; Technology; Testing; Therapeutic; Therapeutic Index; Therapeutic Studies; Toxic effect; Treatment Efficacy; tumor; tumor growth; Work; Xenograft procedure

There is an urgent need for novel therapies to treat glioblastomas (GBMs), the most common and aggressive primary tumor of the nervous system. Patients diagnosed with these brain tumors typically die within a year and there is no effective treatment available. The laboratory of Dr. Nephi Stella recently discovered a new subclass of indole compounds that activates GPR124, a GPCR with established relevance in tumor pathogenesis. These indoles demonstrate efficacy in both in vitro and in vivo models of GBMs. Notably, no overt toxicity was observed in mice dosed over a three week period. The goal of Stella Therapeutics, a newly formed start-up company, is to develop drugs that target GPR124 and exhibit therapeutic value. Thus, in this proof-of-concept work, they will: Aim 1: Validate an i vitro assay that measures agonist activity at GPR124, format this assay for HTS, and screen two compound libraries. Aim 2: Prioritize hits and perform secondary screens. By the end of this SBIR phase I, Stella Therapeutics will have selected compounds (preferably with more than one scaffold) that are agonists at GPR124, kill GBMs and do not harm healthy cells. Their phase II SBIR will further develop the anti-tumor efficacy of these selected compounds by performing focused medicinal chemistry, testing therapeutic efficacy against state-of-the-art animal models of GBMs and systematically verifying toxicity in small and large animals. The overall goal of Stella Therapeutics is to develop drugs that target GPR124 and ready to treat human GBMs.

Public Health Relevance Statement:
There is an urgent need for novel therapies to treat glioblastomas, the most common and aggressive primary tumor of the nervous system. This SBIR phase I proposal outlines a strategy that employs state-of-the-art drug design approach to identify new compounds that activate a novel receptors expressed by glioblastomas. These compounds will kill glioblastomas without harming healthy cells.

Project Terms:
No Project Terms available.