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Principal Investigator: BRUNO CALABRETTA
Organization: THOMAS JEFFERSON UNIVERSITY
Fiscal Year: 2024
Award: $599,770
Funding agency: National Cancer Institute
Abstract
Philadelphia-positive acute lymhoblastic leukemia (Ph+ ALL) and Ph1-like B-ALL account for most cases of
“high-risk” adult B-ALL. Current therapies with tyrosine kinase inhibitors (TKIs) have improved the outcome of
Ph+ ALL, but resistance to TKIs develops rapidly in most patients. Ph1-like B-ALL is currently treated with
intensive combination chemotherapy but disease relapse is common with a 5-year survival in only ~25% of
patients. As a result, the prognosis of Ph+ ALL and Ph1-like B-ALL remains dismal. In previous studies, we
showed that Ph+ and Ph1-like ALL cells exhibit a selective requirement for CDK6 expression while CDK4
expression is dispensable. CDK6 is the catalytic subunit of the cyclin D/CDK6 complex which is essential for
the G1 to S-phase cell cycle transition and has kinase-independent growth-promoting effects in hematological
malignancies. Our preliminary studies indicate that CDK6 silencing is more effective than CDK6 enzymatic
inhibition in suppressing Ph+ ALL in mice. To block kinase-dependent and independent effects of CDK6, we
have developed CDK4/6-targeted proteolysis-targeting chimera (PROTACs) that inhibit CDK4/6 enzymatic
activity in vitro and promote the preferential degradation of CDK6 over CDK4 in Ph+ and Ph1-like ALL cells,
providing durable suppression of CDK6 function. In this proposal, we will assess the requirement of CDK6 in
Ph+ and Ph1-like ALL by comparing the effects of CDK6 degradation by PROTAC YX-2-107 and
pharmacological inhibition using Palbociclib, an FDA-approved CDK4/6 inhibitor (Aim 1.1). We will also
determine whether the more potent leukemia suppression induced by CDK6 down-regulation in comparison to
CDK6 enzymatic inhibition can be explained by changes in gene expression induced selectively by CDK6
silencing. Such changes involve the histone deacetylase 1(HDAC1) gene and several others involved in
mitochondrial metabolic pathways (Aims 1.2 and 1.3). Although we have been able to achieve high specificity
of CDK6 versus CDK4 targeting and biological/therapeutic effects comparable/superior to Palbociclib ex vivo
and in PDXs of Ph+ ALL, we will continue to improve our lead compound PROTAC YX-2-107 by medicinal
chemistry approaches in order to develop derivatives with enhanced in vivo efficacy. In Aim 2, we will assess
metabolic properties of select CDK6-degrading PROTACs and test their biological/therapeutic effects in Ph+
and Ph1-like ALL cells ex vivo and in mice injected with de novo or relapsed/TKI-resistant patient-derived
Ph+/Ph1-like ALL cells. Collectively, our PROTAC-based approach which leverages the expertise in cancer
biology and medicinal chemistry of the Calabretta and Salvino's laboratories holds promise to develop novel
and more effective therapeutic agents for the treatment of CDK6-dependent high-risk B-ALL in pre-clinical PDX
models and, potentially, in the clinic.
Terms: <21+ years old><Acute><Acute B-Lymphocytic Leukemia><Acute Lymphoblastic Leukemia><Acute Lymphocytic Leukemia><Acute Lymphoid Leukemia><Adult><Adult Human><B cell progenitor acute lymphoblastic leukemia><B-ALL><B-Cell Acute Lymphocytic Leukemia><B-Cell Acute Lymphoblastic Leukemia><B-Cell Lymphoblastic Leukemia><B-cell ALL><B-cell precursor acute lymphoblastic leukemia><Biological><Blood><Blood Plasma><Blood Reticuloendothelial System><CCND1 Protein><CDK4><CDK4 Inhibitor><CDK4 gene><CDK6 protein><CDKN2A Protein><Cancer Biology><Cancer Treatment><Cancers><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cdk4-Associated Protein p16><Cell Cycle><Cell Cycle Negative Regulator Beta><Cell Cycle Proteins><Cell Division Cycle><Cell Division Cycle Proteins><Cell Division Kinase 4><Cell Line><Cell-Cycle Regulatory Proteins><CellLine><Cellular Expansion><Cellular Growth><Clinic><Clinical><Combination Drug Therapy><Complex><Cyclin D1><Cyclin-Dependent Kinase 4><Cyclin-Dependent Kinase Inhibitor 2A><Cyclin-Dependent Kinase Inhibitor p12><Cyclin-Dependent Kinase Inhibitor p16><Cytoplasm><Development><Dose><Down-Regulation><Drug Kinetics><Exhibits><Expression Signature><FDA approved><G1/S-Specific Cyclin D1><Gene Action Regulation><Gene Expression><Gene Expression Profile><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><Generalized Growth><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><Growth><HD1><HDAC1><HDAC1 gene><Half-Life><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><High Throughput Assay><Histone Deacetylase 1><Human><INK4A Gene Product><INK4A Protein><Imatinib><In Vitro><Intervention><Intervention Strategies><Kinases><Knowledge><Laboratories><Lead><Link><Liver Microsomes><MLL rearranged><MLL rearrangement><MLL-rearranged leukemia><Malignant Hematologic Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Medicinal Chemistry><Metabolic><Metabolic Pathway><Mice><Mice Mammals><Mitochondria><Modern Man><Molecular><Multiple Tumor Suppressor-1><Murine><Mus><Mutation><Nuclear><Oral><Outcome><PDX model><PLSTIRE gene product><PRAD1 Protein><PSK-J3><PTK Inhibitors><Patient derived xenograft><Patients><Pb element><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmacokinetics><Philadelphia><Phosphotransferase Gene><Phosphotransferases><Plasma><Plasma Serum><Polychemotherapy><Pre-B-Cell Leukemia><Precursor B Lymphoblastic Leukemia><Precursor Cell Lymphoblastic Leukemia><Precursor Lymphoblastic Leukemia><Prognosis><Proliferating><Property><Protac><Protein CDKN2><Protein MTS1><Protein Tyrosine Kinase Inhibitors><Protein p16><Proteolysis targeting chimeric><Proto-Oncogene Proteins c-bcl-1><RNA Expression><RPD3-Like 1><RPD3L1><Recurrent disease><Reduced Potassium Dependency 3, Yeast, Homolog-Like 1><Relapse><Relapsed Disease><Resistance><Resistance development><Resistant development><Reticuloendothelial System, Serum, Plasma><Role><Route><S Period><S phase><Specificity><Strains Cell Lines><Structure-Activity Relationship><Subgroup><Synthesis Period><Synthesis Phase><TK Inhibitors><Testing><Therapeutic Agents><Therapeutic Effect><Tissue Growth><Transcription><Transphosphorylases><Tyrosine Kinase Inhibitor><acute lymphatic leukemia><acute lymphoblastic leukemia cell><acute lymphocytic leukemia cell><acute lymphogenous leukemia><acute lymphoid leukemia cell><acute lymphomatic leukemia><adulthood><advanced breast cancer><advanced stage breast cancer><anti-cancer therapy><bcl-1 Proto-Oncogene Products><bcl-1 Proto-Oncogene Proteins><bcl1 Proto-Oncogene Proteins><biologic><c-bcl-1 Proteins><cancer therapy><cancer-directed therapy><cdc Proteins><cdk6 gene product><cell growth><chemical structure function><combination chemotherapy><combination pharmacotherapy><cultured cell line><cyclin D><cyclin-dependent kinase 6><developing resistance><developmental><effective therapy><effective treatment><gene expression pattern><gene expression signature><genome mutation><heavy metal Pb><heavy metal lead><high risk><high throughput screening><improved><improved outcome><in vitro activity><in vivo><inhibitor><innovate><innovation><innovative><interventional strategy><intraperitoneal><leukemia><leukemia treatment><leukemic therapy><malignancy><mitochondrial><mouse model><murine model><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><p16(INK4A)><p16-INK4><p16INK4 Protein><p16INK4A Protein><patient derived xenograft model><pharmacologic><pre-clinical><preclinical><proteolysis targeting chimera><prototype><resistant><social role><structure function relationship><therapeutically effective><transcriptional profile><transcriptional signature><validation studies>