Our Research
Defining the genomic landscape and biology of multiple myeloma
During the beginning of his time at the Dana-Farber Cancer Institute, Dr. Carrasco worked in the laboratory of Dr. Ronald DePinho (now at the M.D. Anderson Cancer Center in Houston). He directed his research efforts toward oncogenomics and the genetic mouse modeling of hematologic cancers and generated the first "bona fide" mouse model of histiocytic sarcoma, a highly malignant neoplasm of tissue macrophages using PTEN/INK/ARF conditional knockout mice. Subsequently his studies evolved to focus on multiple myeloma (MM), a malignancy of clonal plasma cells that colonize the bone marrow. Specifically, he used genome-wide array-comparative genomic hybridization (a-CGH) to characterize the multiple MM genomes, and generated a novel murine transgenic model of MM using the X-box binding protein 1 (XBP-1). These studies provided new insights into the roles of PTEN and INK-ARF tumor suppressor genes in mouse hematolymphoid development and XBP-1 gene in plasma cell development and pathogenesis of MM. In addition, these studies provided a comprehensive and integrated view of genes that are defective in human MM.
Translating cancer genomics into therapeutic interventions in multiple myeloma
The main focus of the Carrasco Lab’s research is to investigate the role of the Wnt/β-catenin/BCL9 transcriptional complex in the pathogenesis of MM. Wnt signaling underlies the pathogenesis of a broad range of human cancers including carcinomas and hematological malignancies such as MM, yet the development of targeted therapies to disrupt the pathway has remained a formidable challenge due to (i) the toxicities associated with disrupting the pathway’s homeostatic functions and (ii) the large protein interaction surfaces involved. BCL9 is a co-activator of β-catenin-mediated transcription and is highly expressed in tumors but not in their cells of origin, presenting an opportunity to selectively block oncogenic Wnt activity. Having observed in our previous studies that BCL9 is frequently amplified and over-expressed in MM, we began to focus intensively on the role of this Wnt/β-catenin transcriptional co-activator in MM pathogenesis. Our team was the first to show that BCL9 functions as an oncogene that promotes MM progression by conferring enhanced proliferative, metastatic and angiogenic properties to myeloma cells. We next showed that Cyclophilin A (CyPA) is a downstream transcriptional target of the Wnt/β-catenin/BCL9 complex that is secreted by endothelial, but not other, bone marrow cells, and that this secreted factor (eCyPA) promotes pleiotropic signaling changes in MM, including enhanced expression of CD147, the known surface receptor of eCyPA, thereby enhancing the migration, proliferation, and bone marrow homing of MM cells. Having shown that BCL9 drives β-catenin signaling through a direct binding interaction mediated by its α-helical homology domain-2, we found in collaboration with Dr. Loren Walensky at the DFCI that a small “stapled” peptide called Stabilized Alpha-Helix of BCL9 (SAH-BCL9) targets β-catenin, dissociates native β-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and elicits mechanism-based antitumor responses. The clinical translation potential of this approach was underscored by the ability of SAH-BCL9 to effectively suppress the growth, angiogenesis, invasion, and metastasis of MM in vivo. Overall these studies highlight an important role of the Wnt/β-catenin/BCL9 transcriptional complex in MM disease progression and bone marrow homing, and provide compelling proof-of-concept for an innovative pharmacologic strategy to inhibit oncogenic Wnt signaling in MM as well as other cancers with dysregulated Wnt activity via targeted disruption of BCL9/β-catenin complex.
Defining the role of miRs in the pathogenesis of multiple myeloma
A secondary focus of our laboratory is to investigate the role of miRs in the pathogenesis of MM. MiRs are small (~22nt) noncoding RNAs that negatively regulate protein-coding gene expression by targeting mRNA degradation or translation inhibition. Dysregulation of miR expression is frequently observed in human cancers including MM, and has been associated with progressive disease, metastasis, drug resistance, and poor clinical outcome suggesting an important role of miRs in tumor progression. MiRs can function as either tumor suppressors or oncogenes, and have aroused interest as potential developmental foci for cancer therapy. In our recent studies we have demonstrated that the miR-30-5p family is frequently downregulated in MM and functions as a tumor suppressor and novel therapeutic tool by targeting oncogenic Wnt/β-catenin/BCL9 pathway, in addition we have found that the miR-221-222 family is frequently overexpressed in MM and anti-miR-221-222 therapy abrogates dexamethasone resistance by targeting the PUMA/BAK/BAX pathway. These studies point for the first time to a key role of the miR-30-5p and miR-221-222 families in the pathogenesis of MM, and provide compelling proof-of-concept for the potential exploitation of their role in MM therapy.
During the beginning of his time at the Dana-Farber Cancer Institute, Dr. Carrasco worked in the laboratory of Dr. Ronald DePinho (now at the M.D. Anderson Cancer Center in Houston). He directed his research efforts toward oncogenomics and the genetic mouse modeling of hematologic cancers and generated the first "bona fide" mouse model of histiocytic sarcoma, a highly malignant neoplasm of tissue macrophages using PTEN/INK/ARF conditional knockout mice. Subsequently his studies evolved to focus on multiple myeloma (MM), a malignancy of clonal plasma cells that colonize the bone marrow. Specifically, he used genome-wide array-comparative genomic hybridization (a-CGH) to characterize the multiple MM genomes, and generated a novel murine transgenic model of MM using the X-box binding protein 1 (XBP-1). These studies provided new insights into the roles of PTEN and INK-ARF tumor suppressor genes in mouse hematolymphoid development and XBP-1 gene in plasma cell development and pathogenesis of MM. In addition, these studies provided a comprehensive and integrated view of genes that are defective in human MM.
Translating cancer genomics into therapeutic interventions in multiple myeloma
The main focus of the Carrasco Lab’s research is to investigate the role of the Wnt/β-catenin/BCL9 transcriptional complex in the pathogenesis of MM. Wnt signaling underlies the pathogenesis of a broad range of human cancers including carcinomas and hematological malignancies such as MM, yet the development of targeted therapies to disrupt the pathway has remained a formidable challenge due to (i) the toxicities associated with disrupting the pathway’s homeostatic functions and (ii) the large protein interaction surfaces involved. BCL9 is a co-activator of β-catenin-mediated transcription and is highly expressed in tumors but not in their cells of origin, presenting an opportunity to selectively block oncogenic Wnt activity. Having observed in our previous studies that BCL9 is frequently amplified and over-expressed in MM, we began to focus intensively on the role of this Wnt/β-catenin transcriptional co-activator in MM pathogenesis. Our team was the first to show that BCL9 functions as an oncogene that promotes MM progression by conferring enhanced proliferative, metastatic and angiogenic properties to myeloma cells. We next showed that Cyclophilin A (CyPA) is a downstream transcriptional target of the Wnt/β-catenin/BCL9 complex that is secreted by endothelial, but not other, bone marrow cells, and that this secreted factor (eCyPA) promotes pleiotropic signaling changes in MM, including enhanced expression of CD147, the known surface receptor of eCyPA, thereby enhancing the migration, proliferation, and bone marrow homing of MM cells. Having shown that BCL9 drives β-catenin signaling through a direct binding interaction mediated by its α-helical homology domain-2, we found in collaboration with Dr. Loren Walensky at the DFCI that a small “stapled” peptide called Stabilized Alpha-Helix of BCL9 (SAH-BCL9) targets β-catenin, dissociates native β-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and elicits mechanism-based antitumor responses. The clinical translation potential of this approach was underscored by the ability of SAH-BCL9 to effectively suppress the growth, angiogenesis, invasion, and metastasis of MM in vivo. Overall these studies highlight an important role of the Wnt/β-catenin/BCL9 transcriptional complex in MM disease progression and bone marrow homing, and provide compelling proof-of-concept for an innovative pharmacologic strategy to inhibit oncogenic Wnt signaling in MM as well as other cancers with dysregulated Wnt activity via targeted disruption of BCL9/β-catenin complex.
Defining the role of miRs in the pathogenesis of multiple myeloma
A secondary focus of our laboratory is to investigate the role of miRs in the pathogenesis of MM. MiRs are small (~22nt) noncoding RNAs that negatively regulate protein-coding gene expression by targeting mRNA degradation or translation inhibition. Dysregulation of miR expression is frequently observed in human cancers including MM, and has been associated with progressive disease, metastasis, drug resistance, and poor clinical outcome suggesting an important role of miRs in tumor progression. MiRs can function as either tumor suppressors or oncogenes, and have aroused interest as potential developmental foci for cancer therapy. In our recent studies we have demonstrated that the miR-30-5p family is frequently downregulated in MM and functions as a tumor suppressor and novel therapeutic tool by targeting oncogenic Wnt/β-catenin/BCL9 pathway, in addition we have found that the miR-221-222 family is frequently overexpressed in MM and anti-miR-221-222 therapy abrogates dexamethasone resistance by targeting the PUMA/BAK/BAX pathway. These studies point for the first time to a key role of the miR-30-5p and miR-221-222 families in the pathogenesis of MM, and provide compelling proof-of-concept for the potential exploitation of their role in MM therapy.
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©2003-2024 Carrasco Lab at Dana-Farber Cancer Institute
©2003-2024 Carrasco Lab at Dana-Farber Cancer Institute