Multiple myeloma (MM) remains an incurable disease. Although most patients respond to initial treatment, drug resistance develops eventually. Circulating tumor cells in the blood of patients with MM (myeloma CTCs) hold the promise of representing a minimally invasive window into the genetics of MM, and have been implicated as a reservoir of drug-resistant disease as well as prognostic markers. However, little is known about the mutations these cells harbor. Obtaining genetic information from myeloma CTCs provides an opportunity to follow genetic evolution of MM in real time, to predict responses to treatment, and to identify genetic alterations that lead to drug resistance. The objective of this KO8 proposal is to investigate the nature of myeloma CTCs, to determine how they relate to primary MM cells in the bone marrow, and to identify how the genetic profile of myeloma CTCs evolves over time and in response to therapeutic drugs in MM patients. This approach will establish a framework for early detection of genetic resistance in the blood of MM patients and identify targets for therapeutic intervention. I am a medical hematologist/oncologist with a PhD and prior research experience in immunology who is seeking K08 support for mentored research in Dr. Todd Golub's laboratory. The K08 award will provide the protected time I need for advanced training prior to transitioning to an independent investigator position. Under Dr. Golub's mentorship I intend to learn modern tools for genomic analysis of cancers and experimental skills to establish genetic alterations as promising candidates for development of cancer therapeutics. I will be guided by my co-mentor Dr. Kenneth Anderson, in selecting appropriate alterations and therapeutics for translation into clinical trials. I will devote a minium of 80% of my time to a focused research program in myeloma genomics and will complement this with 20% of my effort dedicated to clinical care of patients with hematologic malignancies. DFCI and the Broad Institute of MIT and Harvard are internationally recognized research institutions with expert researchers in the areas of stem cell biology, hematopoiesis, and cancer cell biology. The division of Medical Oncology at DFCI has a distinguished record of training physician-scientists. I have assembled an Advisory Committee of internationally recognized experts in the field of cancer genomics, single cell analysis, myeloma biology, and clinical research that will monitor my progress. I will also engage in training activities including seminar series, international meetings and formal coursework to acquire additional skills in translational investigation and computational genomic analysis. This research proposal is part of a structured plan with scientific, technical, clinical training and career development components. The career development plan builds upon my prior research and clinical experiences with the goal of ensuring that I acquire the expertise required to become a successful, independent investigator at an academic center.

Public Health Relevance

Multiple myeloma is an incurable and genetically highly diverse cancer, with different cancer mutations present in different myeloma cells of the same patient, and a mutational spectrum that evolves over time, particularly when the patient is treated. This proposal seeks to determine the mutational spectrum in multiple myeloma patients and investigate how it changes over time and with treatment, simply by drawing a tube of blood. I will use novel technology that we have developed to perform DNA sequencing from circulating multiple myeloma cells, and compare the results to the genetic profile of primary multiple myeloma in the bone marrow; we anticipate that this approach will enable the identification of genomic mechanisms that lead to drug resistance, and identify the most promising treatment strategies in patients with multiple myeloma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA191026-02
Application #
9108344
Study Section
Subcommittee I - Transistion to Independence (NCI)
Program Officer
Lim, Susan E
Project Start
2015-07-09
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
Guo, Guangwu; Raje, Noopur S; Seifer, Charles et al. (2018) Genomic discovery and clonal tracking in multiple myeloma by cell-free DNA sequencing. Leukemia 32:1838-1841
Holstein, Sarah A; Avet-Loiseau, Hervé; Hahn, Theresa et al. (2018) BMT CTN Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling: Summary and Recommendations from the Organizing Committee. Biol Blood Marrow Transplant 24:641-648
Waldschmidt, Johannes M; Anand, Praveen; Knoechel, Birgit et al. (2018) Comprehensive characterization of circulating and bone marrow-derived multiple myeloma cells at minimal residual disease. Semin Hematol 55:33-37
Adalsteinsson, Viktor A; Ha, Gavin; Freeman, Samuel S et al. (2017) Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat Commun 8:1324
Mishima, Yuji; Paiva, Bruno; Shi, Jiantao et al. (2017) The Mutational Landscape of Circulating Tumor Cells in Multiple Myeloma. Cell Rep 19:218-224
Lohr, Jens G; Kim, Sora; Gould, Joshua et al. (2016) Genetic interrogation of circulating multiple myeloma cells at single-cell resolution. Sci Transl Med 8:363ra147