This Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) provides $631,492 to The University of Kentucky Research Foundation to identify nicotinamide N-methyltransferase (NNMT) as a novel therapeutic target for treating triple-negative breast cancer (TNBC). The research aims to define how NNMT promotes TNBC cell survival and metastasis, evaluate the efficacy of a newly developed NNMT inhibitor, and determine NNMT's function and therapeutic potential...
This Project Grant award from the National Cancer Institute, funded under the Cancer Treatment Research program (CFDA 93.395), is focused on developing peptide drug conjugates to treat triple negative breast cancer (TNBC). The goal is to create novel peptide-based drug delivery systems to improve the efficacy of chemotherapies for this aggressive form of breast cancer. The $530,358 award to Molecular Theranostics LLC will support two key objectives: 1) synthesizing and characterizing a peptide...
This Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) provides $400,000.00 to Promilead, LLC in Columbia, South Carolina to evaluate the use of a small-molecule compound USCYL01 as a means to boost the efficacy of immune checkpoint inhibitor (ICI) and chemotherapy treatments for triple negative breast cancer (TNBC). The key objectives are to: 1) assess the toxicity and pharmacokinetic properties of USCYL01 in vitro and in vivo, and 2) test...
This $398,728 Project Grant awarded by the National Cancer Institute (NCI) under the Cancer Treatment Research program (CFDA 93.395) supports the development of a novel homologous recombination (HR) inhibitor, CP-8, to sensitize triple-negative breast cancer (TNBC) cells to DNA-damaging agents. The project aims to examine the synergy of CP-8 with various DNA-damaging therapies, including PARP inhibitors and ionizing radiation, in TNBC cell lines, patient-derived xenograft models, and in vivo...
This federal Project Grant award from the National Cancer Institute (CFDA 93.395 Cancer Treatment Research) provides $622,329 to Virginia Commonwealth University (VCU) to conduct research aimed at modulating growth, progression, and metastasis in breast cancer by inhibiting the MDA-9 protein. The key products and services to be delivered include: Formulating the PDZ1I small molecule inhibitor of MDA-9 for clinical applications, including developing a novel nanocrystal technology (PDZ1I-nano) and...
This Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) supports the development of a novel CD4 TCR-engineered T cell immunotherapy for the treatment of triple-negative breast cancer (TNBC). The total funding amount is $1,001,029 for the period from September 20, 2024 to August 31, 2026. The key products or services to be delivered under this award include: 1) Generation of a GMP-grade master cell bank and viral particles for the IMT-422 (CD4...
This Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) provides $215,311 to the University of Texas Health Science Center at Houston to conduct preclinical research on antibody-drug conjugates (ADCs) targeting the GPR56 protein for the treatment of triple-negative breast cancer (TNBC). The key objectives are to: 1) Generate and evaluate the cell-killing efficacy of GPR56-targeted ADCs in TNBC cell lines; 2) Assess the safety and efficacy of the lead...
This $148,500 Project Grant award from the National Cancer Institute (CFDA 93.396 - Cancer Biology Research) supports research to investigate the role of the protein kinase PBK in driving tumor growth and metastasis in triple-negative breast cancer (TNBC). The research, conducted by the University of Alabama at Birmingham, aims to determine the in vivo effects of PBK inhibition on TNBC tumor growth and metastasis, as well as evaluate the efficacy of a PBK inhibitor for TNBC treatment. The...
This federal Project Grant award from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) provides funding of $619,764 to the University of Wisconsin-Madison to develop new combination immunotherapy strategies for treating triple-negative breast cancer (TNBC). The key objectives are to: 1) Increase the tumor-specific accumulation of a platelet-mediated immune checkpoint inhibitor delivery system (P-aPDL1) by triggering local thrombus formation at the TNBC site, and 2)...
This $400,000 Project Grant awarded by the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) supports the development and testing of a novel nanoparticle formulation of the mediator kinase inhibitor SNX631-6 for the treatment of peritoneal ovarian cancer metastases. The goal is to optimize the nanoparticle delivery system to improve the pharmacokinetics and efficacy of this targeted cancer therapy when administered intraperitoneally, compared to oral administration. The...
DEVELOPMENT OF VNLG-152R AS NOVEL THERAPEUTIC FOR TRIPLE NEGATIVE BREAST CANCER - PROJECT TITLE: DEVELOPMENT OF MNK1/2 DEGRADER, VNLG-152 AS NOVEL THERAPEUTIC FOR TRIPLE NEGATIVE BREAST CANCER PROJECT SUMMARY/ABSTRACT CURRENTLY, THERE ARE NO EFFECTIVE THERAPIES FOR PATIENTS WITH TRIPLE NEGATIVE (ERA, PR, AND HER2 NEGATIVE) BREAST CANCER (TNBC), AN AGGRESSIVE AND HIGHLY METASTATIC DISEASE. ACTIVATION OF EUKARYOTIC INITIATION FACTOR 4E (EIF4E) BY MITOGEN-ACTIVATED PROTEIN KINASE (MAPK)-INTERACTING KINASES 1 AND 2 (MNK1/2) PLAY A CRITICAL ROLE IN THE DEVELOPMENT, PROGRESSION AND METASTASIS OF TNBC. IT IS IMPORTANT TO NOTE THAT MNK1/2 ACTIVITY AND THE PHOSPHORYLATION OF EIF4E ARE DISPENSABLE FOR NORMAL DEVELOPMENT, THUS MAKING MNK1/2 ATTRACTIVE THERAPEUTIC TARGETS. WE HAVE RECENTLY SHOWN THAT PROPRIETARY ISOPRENE PHARMACEUTICALS INC. (IPI) NOVEL RETINAMIDES (NRS) EXHIBIT EXQUISITE ANTI- TNBC ACTIVITIES IN VITRO AND IN VIVO AGAINST MDA-MB-231 TUMOR XENOGRAFTS, METASTASIS AND TNBC PATIENT-DERIVED XENOGRAFTS (PDX) IN MICE. TO TRANSLATE THESE FINDINGS TOWARDS HUMAN CLINICAL TRIALS, WE HAVE IDENTIFIED NOVEL COMPOUNDS, RACEMIC VNLG-152 (VNLG-152R), WITH THREE BACK-UP COMPOUNDS (VNLG-153, VNHM-1-73 AND VNHM- 1-81) THAT INDUCE MNK1/2 DEGRADATION (WITH CONSEQUENT DEPLETION OF ONCOGENIC PEIF4E). BY TARGETING MNK1/2 PROTEIN DEGRADATION, VNLG-152R POTENTLY INHIBITED BOTH MNK-EIF4E AND MTORC1 SIGNALING PATHWAYS AND STRONGLY REGULATES DOWNSTREAM FACTORS INVOLVED IN CELL CYCLE REGULATION, APOPTOSIS, PRO-INFLAMMATORY CYTOKINES/CHEMOKINES SECRETION, EPITHELIAL-MESENCHYMAL TRANSITION (EMT) AND METASTASIS. MOST IMPORTANTLY, ORALLY BIOAVAILABLE VNLG-152R EXHIBITED REMARKABLE DOSE-DEPENDENT ANTITUMOR (91 TO 100% GROWTH INHIBITION) AND ANTIMETASTATIC (~80% INHIBITION) ACTIVITIES AGAINST CELL LINE AND PATIENT-DERIVED TNBC XENOGRAFT MODELS, WITH NO APPARENT HOST TOXICITY. COLLECTIVELY, THESE STUDIES DEMONSTRATE THAT TARGETING MNK-EIF4E/MTORC1 SIGNALING WITH A POTENT MNK1/2 DEGRADER, VNLG-152R, IS A NOVEL THERAPEUTIC STRATEGY THAT CAN BE DEVELOPED AS MONOTHERAPY FOR THE EFFECTIVE TREATMENT OF PATIENTS WITH BOTH PRIMARY AND METASTATIC TNBC. WITH SUPPORT FROM MARYLAND INNOVATIVE INITIATION (MII) AWARD WE HAVE SUCCESSFULLY COMPLETED ALL THE AIMS OF OUR SBIR PHASE-1-TYPE R & D STUDY AS WELL AS CONDUCTED MANY ADDITIONAL STUDIES THAT WERE NOT ORIGINALLY ANTICIPATED. WE NOW SEEK DIRECT-TO-PHASE II SBIR SUPPORT TO ADVANCE VNLG-152R THROUGH VARIOUS IND- ENABLING PRE-CLINICAL DEVELOPMENT ACTIVITIES. OUR GOAL IS TO DEVELOP VNLG-152R AS AN ORAL TARGETED ANTICANCER AGENT FOR EFFECTIVE TREATMENT OF THE DIFFICULT-TO-TREAT PRIMARY AND METASTATIC TNBC. THE SPECIFIC AIMS FOR THIS DIRECT-TO-PHASE II SBIR PROPOSAL ARE: 1. SYNTHESIZE 300 G OF NON-GMP VNLG-152R FOR PRECLINICAL STUDIES, INCLUDING ANALYTICAL CHARACTERIZATION, FORMULATION AND USE THIS AGENT TO SUPPORT GLP PRECLINICAL STUDIES. 2. CONDUCT ANCILLARY PHARMACOLOGY WITH VNLG-152R USING IN VITRO AND IN VIVO MODELS OF TNBC. 3. CONDUCT IND-ENABLING STUDIES, INCLUDING GLP TOXICITY AND TOXICOKINETICS STUDIES IN TWO RELEVANT ANIMAL SPECIES TO IDENTIFY APPROPRIATE STARTING VNLG-152R DOSE FOR USE IN FIRST-IN-HUMAN PHASE I CLINICAL TRIALS AND PREPARE THE IND FILING. UPON SUCCESSFUL COMPLETION OF THESE STUDIES AN FDA INVESTIGATIONAL NEW DRUG (IND) APPLICATION WILL BE FILED.