Validating novel biologic mediators and therapeutic targets in t(4;14) myeloma

Robert Orlowski headshot

Bob Orlowski, MD, PhD

Director of Myeloma, and Professor of Medicine in the Departments of Lymphoma/Myeloma and Experimental Therapeutics, Division of Cancer Medicine,
University of Texas, MD Anderson Cancer Center

The University of Texas MD Anderson Cancer Center logo

Our team has been performing single cell RNA sequencing (scRNA-Seq) of CD138+ myeloma cells and CD138- tumor microenvironment (TME) cells, as well as single cell B-cell (scBCR-Seq) and T-cell receptor sequencing (scTCR-Seq) and genomic sequencing in studies of myeloma precursors and in the relapsed/refractory setting. Leveraging our large database from these studies, we are analyzing scRNA-Seq data from t(4;14) patients and compared these to non-t(4;14) patients. In addition to the up-regulation of FGFR3 and NSD2, which are known to be dysregulated in t(4;14), we are studying the biological roles and relevance of other genes that are statistically and uniquely dysregulated in the neoplastic cells. These studies will also be extended to the CD138- cells in the TME that are characteristic of t(4;14) in the precursor, newly diagnosed, and relapsed and/or refractory settings, incorporating also our scBCR- and scTCR-Seq data.

Fenghuang (Frank) Zhan headshot

Fenghuang (Frank) Zhan, MD, PhD

Executive Director of Myeloma Center Basic Research,
the Morrison Family Endowed Chair,
Co-Leader of Cancer Biology Program at the Cancer Institute, Professor of Department of Internal Medicine, University of Arkansas Medical Sciences

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The translocation t(4;14) is one of four genetic high-risk subtypes of multiple myeloma (MM), which have a notoriously short survival with conventional treatment modalities. Increasing evidence suggests that genetic heterogeneity in MM cells accounts for divergent clinical outcomes. Novel classes of drugs along with Autologous Stem Cell Transplantation (ASCT) have increased patient survival rates however, MM patients carrying a t(4;14) translocation are at least partially resistant to such treatments. Therefore, there is an urgent need to develop novel treatments specifically targeting these high-risk subtypes. As part of a group effort with the labs of Dr. Orlowski and Dr. Yi, we will collaborate to develop novel therapies for t(4;14) translocation myeloma. The Myeloma Center at the UAMS Winthrop P. Rockefeller Cancer Institute site of the collaboration will focus on BCMA/DSG2-CAR-T-dependent target therapy. Our systematic analyses of primary human MM samples and MM cell lines have shown that Desmoglein 2 (DSG2), a trans-membrane glycoprotein is highly expressed on tumor cells derived from MM patients with t(4;14). We expect that BCMA/DSG2 CAR-T-cell treatment can eliminate MM cells without obvious side effects in laboratory mice carrying t(4;14) MM cells. The planned studies should define whether DSG2 is an ideal target to cure MM disease with t(4;14). The ultimate goal of this work is to prepare for a clinical trial of therapeutic targeting BCMA and DSG2 for the high-risk subtype of MM patients who have t(4;14).

Qing Yi headshot

Qing Yi, MD, PhD

Ralph O’Connor Centennial Chair,
Director, Center for Translational Research in Hematological Malignancies
Houston Methodist Neal Cancer Center

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Myeloma patients have benefited from a number of recent therapeutic advancements. However, there remains a high-risk group who still have substantially shorter remission durations and, ultimately, a shorter survival. This population is composed of several molecularly defined subgroups, one of which is patients with a translocation t(4;14). The central goal of our joint effort is to identify and validate new targets and strategies that can be rapidly deployed to the clinic to improve patient outcomes and first convert high-risk myeloma into standard risk disease and, in the longer term, to cure t(4;14) myeloma altogether. This goal will be accomplished through a combination of discovery, translational, and clinical science, which are key areas of expertise for the leaders of this project. Our team already has preliminary data to support the application of a several drugs into the clinic, including methionine adenosyl transferase (MAT2A) inhibitor AG-270, all-trans retinoic acid (ATRA), and the fibroblast growth factor 3 (FGFR3) antibody drug conjugate LY3076226, which will be repurposed and/or redesigned. At Houston Methodist Neal Cancer Center, we are searching for drugs that can sensitize drug-naïve and resensitize drug-resistant multiple myeloma (MM) cells to immunomodulating drugs (IMiDs). We performed a high-throughput screen of 1855 FDA-approved drugs and identified all-trans retinoic acid (ATRA), which alone has no antimyeloma effect, as a potent drug enhancing MM sensitivity to pomalidomide (POM)-induced cytotoxicity in vitro. Interestingly, in the two cell lines we tested that carry the t(4;14) translocation, ATRA significantly enhanced POM-induced cell death. Our aims are to 1) confirm these preliminary results, 2) determine the role of retinoic acid receptors (RARs) and retinoid X receptor (RXRs) in ATRA-mediated sensitization of MM cells to POM, and 3) elucidate the mechanisms underlying t(4;14) MM sensitivity to ATRA+POM-induced cell death.