SBIR-STTR Award

Direct to Phase II

The incidence of esophageal adenocarcinoma (EAC) has tripled over the last 40 years, but five-year overallsurvival is still poor due to late stage diagnosis, metastasis, and high rates of recurrence after standardchemotherapy. Standard-of-care therapy (neoadjuvant chemotherapy, radiation, or both followed byesophagectomy) achieves only 20% response rates, while 80% of patients remain poorly responsive. Recently,we have shown that aberrant activation of Notch1 signaling correlates with poor therapeutic responses andoutcomes in EAC patients and that EAC tumors are dependent upon sustained Notch1 activity. The vast majorityof R&D efforts to inhibit Notch have focused on gamma secretase inhibitors (GSIs), which inhibit all Notchproteins, and as a result cause significant dose-limiting toxicity, largely hampering their clinical utility to date.Thus, there is a significant unmet clinical need for targeted therapies against Notch1-dependent cancers suchas EAC. StemSynergy Therapeutics has identified a first-in-class inhibitor series that binds and inhibits theNotch1 Transcriptional Complex and limits transcription of downstream effectors of Notch1 signaling. We havedemonstrated that only Notch1-dependent EAC cell lines are sensitive to our inhibitors, which blocked the growthof EAC patient-derived xenograft tumors. We further improved pharmacokinetics and specificity to produce ourlead clinical candidate SSTN-302, which is a highly potent and selective inhibitor of Notch1 and inhibits EACtumor growth in vivo. Furthermore, SSTN-302 has promising ADME properties, high oral bioavailability, and mostimportantly - avoids the dose-limiting toxicity of GSIs. This Direct Phase II proposal seeks to determine thepreclinical safety of SSTN-302 for the purposes of advancing a novel Notch1 inhibitor into the clinic.

Public Health Relevance Statement:
PROJECT NARRATIVE Esophageal adenocarcinoma incidence is increasing and remains poorly responsive to current standard-of-care therapy. Aberrant activation of Notch1 signaling correlates with poor therapeutic responses and outcomes in EAC patients. We have developed a first in class Notch1-selective inhibitor that we intend to advance into preclinical IND- enabling safety studies with the goal of bringing a targeted therapeutic for EAC to the clinic.

Project Terms:
Aftercare ; After Care ; After-Treatment ; post treatment ; Animals ; inhibitor/antagonist ; inhibitor ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Cells ; Cell Body ; Diagnosis ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Euthanasia ; Mercy Killing ; Exhibits ; Gastrointestinal tract structure ; Alimentary Canal ; Digestive Tract ; GI Tract ; Gastrointestinal Tract ; alimentary tract ; digestive canal ; Goals ; Growth ; Generalized Growth ; Tissue Growth ; ontogeny ; Incidence ; Intestines ; Intestinal ; bowel ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; 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 ; Patients ; Drug Kinetics ; Pharmacokinetics ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Recurrence ; Recurrent ; research and development ; Development and Research ; R & D ; R&D ; Risk ; Rodent ; Rodentia ; Rodents Mammals ; Role ; social role ; Safety ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Specificity ; Testing ; Time ; Tissues ; Body Tissues ; Toxicology ; Genetic Transcription ; Gene Transcription ; RNA Expression ; Transcription ; Generations ; notch protein ; notch ; notch receptors ; Esophagectomy ; excision of the esophagus ; Treatment outcome ; Guidelines ; base ; improved ; Clinical ; Phase ; Series ; Evaluation ; Recovery ; Esophageal Adenocarcinoma ; Adenocarcinoma of the Esophagus ; Therapeutic ; Life ; programs ; ADAM10 protein ; gamma secretase complex ; γ-secretase ; gamma secretase ; Complex ; Oral ; Clinic ; Protocol ; Protocols documentation ; experience ; tumor growth ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Induction Therapy ; NEOADJ ; Neoadjuvant ; Neoadjuvant Treatment ; Neoadjuvant Therapy ; Toxicities ; Toxic effect ; novel ; Position ; Positioning Attribute ; Maximal Tolerated Dose ; Maximally Tolerated Dose ; Maximum Tolerated Dose ; Property ; response ; Adverse effects ; Cancer Treatment ; Malignant Neoplasm Therapy ; Malignant Neoplasm Treatment ; anti-cancer therapy ; anticancer therapy ; cancer-directed therapy ; cancer therapy ; Molecular Interaction ; Binding ; Oncogenesis ; tumorigenesis ; Dose ; Data ; Dose-Limiting ; in vivo ; therapy outcome ; therapeutic outcome ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Validation ; Pathologic ; Monitor ; Process ; Development ; developmental ; safety study ; paralogous gene ; paralog ; pre-clinical ; preclinical ; tumor xenograft ; chemotherapy ; stem ; tumor ; new therapeutic target ; new drug target ; new druggable target ; new pharmacotherapy target ; new therapy target ; novel drug target ; novel druggable target ; novel pharmacotherapy target ; novel therapeutic target ; novel therapy target ; standard of care ; treatment response ; response to treatment ; therapeutic response ; preclinical safety ; pre-clinical safety ; intestinal homeostasis ; gastrointestinal homeostasis ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; clinical investigation ; Formulation ; small molecule inhibitor ; clinical candidate ; preclinical development ; pre-clinical development ; lead candidate ; Chemotherapy and/or radiation ; Chemotherapy and Radiation ; patient derived xenograft model ; PDX model ; Patient derived xenograft ;