Saturday, December 21, 2024
12/21/2024
Abstract Melanoma is the deadliest form of skin cancer, affecting an estimated 1.2 million Americans. The disease has a high propensity for dissemination, and metastatic melanoma has a dismal prognosis, with a median survival of only 5–8 months. Healthcare costs for melanoma in 2021 are projected to reach nearly $4 billion, with a rising incidence rate. Despite considerable efforts in recent years to develop more effective targeted and immunotherapies against melanoma, the 5-year survival rate for stage IV melanoma patients remains around 20%. Thus, there is a significant unmet clinical need for novel treatment strategies to improve outcomes for patients with melanoma. Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase and scaffolding protein considered to be a highly promising cancer drug target due to its involvement in multiple hallmarks of cancer, including migration, invasion, metastasis, apoptosis, proliferation, angiogenesis, and immune-cell suppression. FAK is overexpressed in 60–80% of multiple solid tumors, including breast, colon, ovarian, and pancreatic cancer, and is massively upregulated in human melanoma samples. Despite its potential as a therapeutic target, the FAK inhibitors developed to date only target the ATP-binding pocket of the kinase domain and have shown little clinical success. However, recent proof-of-principle studies have shown that the focal adhesion targeting (FAT) scaffolding domain of FAK is an essential regulator of melanoma survival, growth, and metastasis. Additionally, FAKnostics has preliminary data showing that FAT domain inhibition selectively decreases viability of NRAS-mutant melanoma cells, a subset of melanoma that represents 20-30% of all cases and has no effective targeted therapies. On the basis of these findings, FAKnostics has identified a first-in-class series of peptidic FAK inhibitors that directly target the FAT domain of FAK and have significant anti-cancer effects in NRAS- mutant melanoma. In Phase I, FAKnostics identified a stapled peptide candidate with ~5,000-fold higher binding affinity to the FAK FAT domain versus the native paxillin LD2 motif. Furthermore, we have demonstrated proof- of-concept of this approach by confirming in vivo efficacy in a syngeneic mouse model. Through this Phase II project, FAKnostics seeks to continue the development of this treatment approach through the following specific aims: 1) Optimize lead peptides through iterations of medicinal chemistry to improve cellular potency and drug- like properties; 2) Evaluate top optimized peptides in pharmacokinetic and in vivo efficacy studies to select preclinical candidate peptide; 3) Complete formulation studies of final clinical candidate peptide and evaluate safety/toxicology in rats; and 4) Determine patient population suitable for clinical trials using melanoma patient- derived xenograft and syngeneic efficacy modelsand determine optimal combinational treatment regimen. Upon successful completion of these aims, FAKnostics intends to initiate GMP manufacturing and GLP safety/toxicology studies in preparation for an FDA IND application and a clinical trial.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).