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Principal Investigator: STACY W BLAIN
Organization: CONCARLO HOLDINGS, LLC
Fiscal Year: 2020
Award: $320,217
Funding agency: National Cancer Institute
Project Summary/Abstract
The goal of this SBIR is to develop a novel drug, IpY, to improve advanced ER/PR+, Her2- breast cancer
outcomes. Almost 250,000 US women will be diagnosed this year, and over 40,000 will die, suggesting that
despite advances in treatments, breast cancer remains a significant health burden. ER/PR+, Her2- tumors
occur in approximately 40% of breast cancer patients, are associated with poor survival, and are candidates for
estrogen pathway targeting drugs, such as Letrozole, but clinical outcomes for this patient population are still
inadequate: Roughly half of treated ER/PR+ patients will develop metastatic disease within 5 y. CDK4
targeting drugs (CDK4i), like Palbociclib, were recently approved in combination with Letrozole or Fulvestrant
as a frontline therapy for metastatic ER/PR+, Her2- patients. However, even these therapies do not represent
“cure”. While combined ER and CDK4 inhibition treatment significantly extends Progression Free Survival
(PFS), those treated eventually develop resistance to the combination and the Overall Survival (OS) of these
patients is unchanged, suggesting that drug resistance remains an unmet need. Resistance develops because
of compensation by another protein, CDK2, suggesting that to be effective, therapies must be developed to
inhibit BOTH CDK4 and CDK2. The drug, IpY, is a novel peptide-lipid formulation, which targets a different
protein, p27Kip1, that in turn causes inhibition of both CDK4 and CDK2, and represents the first therapeutic
that would accomplish this. IpY reduces proliferation in breast cancer tissue culture models and in vivo,
prevents drug resistance in animal models. IpY is innovative because 1) the p27 target is unique, so blocking it
results in a specific treatment with fewer off-target effects, resulting in less toxicity, 2) IpY targets acquired drug
resistance by hitting both CDK4 and CDK2 at the onset, resulting in a prolonged response to the drug, which
should increase patient survival and 3) IpY can be used alone or in combination with Palbociclib, to make this
already improved therapy better. The hypothesis to be tested in this SBIR project is that IpY can be delivered
efficiently and with limited toxicity in vivo following systemic IV administration to clinically relevant mouse
models, thereby demonstrating the feasibility of using this novel liposomal peptide nanoparticle approach in
more advanced pre-clinical studies. Specifically, this SBIR will 1) demonstrate that IpY reduces tumor
progression and increases OS in genetically engineered models (GEM) that develops breast cancer in
an immunocompetent background, and 2) Demonstrate that IpY has a stable blood half-life and is
delivered to tumors in different models. In Phase II, Concarlo will utilize CROs for the IND-enabling
pharmacokinetics/ADME (absorption, distribution, metabolism, excretion) and Good Laboratory Practice
(GLP)-compliant toxicology studies. Sales of Palbociclib were $1 billion in Q1 2019, but resistant patients had
no additional therapeutic options. Concarlo is generating a CDK4/6/2 and NOT CDK1 inhibitor to deal with the
resistance seen in these patients. As such there is no current competition for IpY.
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Terms: <4T1><Abscission><Affect><Animal Model><Animal Models and Related Studies><Animals><Autopsy><Biodistribution><Bittner Virus><Blood><Blood Reticuloendothelial System><Blood Serum><Brain><Brain Nervous System><Breast><Breast Cancer><Breast Cancer Model><Breast Cancer Patient><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><Breast tumor model><Bypass><CDC2><CDC2 Protein Kinase><CDC2 gene><CDK1><CDK2><CDK2 gene><CDK4><CDK4 Inhibitor><CDK4 gene><CDKN2A Protein><Cancer Burden><Cancer cell line><Cancers><Cardiac><Cdk4-Associated Protein p16><Cell Cycle Controller CDC2 Gene><Cell Cycle Controller cdc2><Cell Cycle Negative Regulator Beta><Cell Division Control Protein 2 Homolog><Cell Division Cycle 2><Cell Division Cycle 2 Protein><Cell Division Kinase 2><Cell Division Kinase 4><Chemistry><Clinical><Clinical Chemistry><Clinical Trials><Compensation><Cy5><Cyclin-Dependent Kinase 1><Cyclin-Dependent Kinase 2><Cyclin-Dependent Kinase 4><Cyclin-Dependent Kinase Inhibitor 2A><Cyclin-Dependent Kinase Inhibitor p12><Cyclin-Dependent Kinase Inhibitor p16><Diagnosis><Disease><Disease remission><Disorder><Dose><Drug Kinetics><Drug Targeting><Drug resistance><Drugs><ER Positive><ER+><Encephalon><Estrogen Therapy><Estrogen receptor positive><Estrogens><Excision><Excretory function><Exhibits><Extirpation><Faslodex><Femara><Financial compensation><Formulation><Fulvestrant><Generalized Growth><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Goals><Growth><Half-Life><Head and Neck><Head and neck structure><Health><Hematology><Human><ICI 182,780><ICI 182780><INK4A Gene Product><INK4A Protein><IVIS SpectrumCT><IVIS imaging><IVIS optical imaging><IVIS spectral imaging><IVIS spectrum><IVIS system><Immune><Immune response><Immunes><Immunocompetent><Immunological response><Intermediary Metabolism><Intravenous><Letrozole><Licensing><Limited Resection Mastectomy><Lipids><Liposomal><Liposomes><Local Excision Mastectomy><Lumpectomy><MMTV><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Cancer Virus><Mammary Neoplasms><Mammectomy><Mastectomy><Mediating><Medication><Metabolic Processes><Metabolism><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Metastatic breast cancer><Mice><Mice Mammals><Modeling><Modern Man><Mouse Mammary Tumor Virus><Multiple Tumor Suppressor-1><Murine><Mus><NSCLC><NSCLC - Non-Small Cell Lung Cancer><National Cancer Burden><Neoplasm Metastasis><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Nonsmall Cell Lung Carcinoma><Oncology><Oncology Cancer><Organ><Outcome><PSK-J3><Pancreas><Pancreatic><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Phase><Population><Progression-Free Survivals><Protein CDKN2><Protein MTS1><Protein p16><Proteins><Puncture procedure><Punctures><Recombinant DNA Technology><Refractory><Remission><Removal><Resistance><Resistance development><Resistant development><SBIR><Sales><Secondary Neoplasm><Secondary Tumor><Serum><Small Business Innovation Research><Small Business Innovation Research Grant><Subgroup><Surgical Removal><System><Testing><Therapeutic><Therapeutic Estrogen><Time><Tissue Growth><Toxic effect><Toxicities><Toxicology><Transfusion><Tumor Volume><V-Ras-Ha><V-Rasha><Validation><Woman><absorption><acquired drug resistance><bone><breast lumpectomy><cancer metastasis><cancer progression><cancer type><cdc2 gene product><cdc2+ Protein><cdk1 Kinase><clinical relevance><clinically relevant><combat><commercialization><cyanine dye 5><developing resistance><drug resistant><drug/agent><effective therapy><effective treatment><estrogen treatment><excretion><genetically engineered><good laboratory practice><host response><immune competent><immunoresponse><improved><in vitro activity><in vivo><in vivo imaging system><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><malignancy><malignant breast neoplasm><malignant breast tumor><mammary cancer model><mammary tumor><mammary tumor model><milk agent><model of animal><model organism><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><necropsy><neoplasm progression><neoplasm/cancer><neoplastic progression><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><nonsmall cell lung cancer><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><ontogeny><p16(INK4A)><p16-INK4><p16INK4 Protein><p16INK4A Protein><p34 Protein Kinase><p34 Protein Kinase Gene><p34(CDC2) Gene><p34CDC2><pathway><patient population><peptide drug><postmortem><pre-clinical study><precision medicine><precision-based medicine><preclinical study><prevent><preventing><resection><residence><residential building><residential site><resistance to Drug><resistance to therapy><resistant><resistant to Drug><resistant to therapy><response><scale up><standard of care><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic peptide><therapeutic resistance><therapy resistant><tissue culture><treated with estrogen><treatment resistance><treatment with estrogen><tumor><tumor cell metastasis><tumor progression>