Kenneth C. Anderson, MD
Kraft Family Professor of Medicine, Harvard Medical School
Office phone: 617-632-2144
Preferred contact method: appointment phone
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Multiple myeloma, Stem cell/ bone marrow transplant
Area of ResearchNovel Biologically Based Therapies for Multiple Myeloma
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215
BiographyDr. Anderson graduated from Johns Hopkins Medical School, trained in internal medicine at Johns Hopkins Hospital, and completed hematology, medical oncology, and tumor immunology training at Dana-Farber Cancer Institute.
He serves as chief of the Division of Hematologic Neoplasia, director of the Jerome Lipper Multiple Myeloma Center, and vice chair of the Joint Program in Transfusion Medicine at Dana-Farber.
- Robert A. Kyle Lifetime Achievement Award, 2005
ResearchNovel Biologically Based Therapies for Multiple Myeloma
Our recent advances in genomics and proteomics in multiple myeloma (MM) have increased our understanding of disease pathogenesis, helped to identify novel therapeutic targets, and provided the scientific rationale for combining targeted therapies to increase tumor-cell cytotoxicity and abrogate drug resistance. Specifically, gene microarray profiling has shown major differences between normal plasma cells and cells from monoclonal gammopathy of unclear significance (MGUS) and MM cells, with further modulations within MM cells and in cells progressing to plasma cell leukemia. Therefore, we have profiled individual patients newly diagnosed with MM in order to tailor targeted therapy for them; it is likely that cocktails of therapeutics will be needed to overcome resistance.
Recognition of the role of the bone marrow (BM) milieu in conferring growth, survival, and drug resistance in MM cells - in both the laboratory and in animal models - has enabled us to establish a new treatment paradigm targeting the tumor cell and its microenvironment. Our studies in a SCID-human mouse model of MM have demonstrated modulations associated with binding of MM cells to the BM microenvironment: upregulation of growth-, survival-, and drug-resistance genes in MM cells; increased adhesion molecule expression on MM cells and bone marrow stromal cells (BMSCs); and increased cytokine transcription and secretion in BMSCs. Thalidomide, the proteasome inhibitor bortezomib, and the novel immunomodulatory drug lenalidamide maintain their cytotoxicity against MM cells even in the BM milieu. They do so by: (1) directly inducing apoptosis of drug-resistant MM cells; (2) decreasing the adhesion of MM cells to BMSCs and extracellular matrix proteins; (3) downregulating the transcription and secretion of cytokines in the BM milieu that mediate tumor cell growth, survival, and migration; (4) inhibiting angiogenesis; and (5) stimulating host antiMM immunity. Each of these drugs has been shown to have antitumor activity in relapsed and refractory MM, whether alone or combined with dexamethasone. Clinical trials have also evaluated their utility earlier in the disease course.
Finally, our correlative gene profiling, proteomic, and signaling studies in tumor cell samples from patients treated with novel agents have identified the mechanisms of sensitivity and resistance, provided the rationale for selection of patients most likely to respond, helped to design combination therapies to enhance sensitivity and overcome resistance in MM cells, and suggested ways to develop more potent, selective, and less toxic targeted therapeutics.
- Hideshima T, Bradner J, Wong J, Chauhan D, Richardson P, Schreiber SL, Anderson KC. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma: therapeutic implications. Proc Natl Acad Sci U S A 2005;102:8567-72.
- Mitsiades CS, Mitsiades N, Bronson RT, Chauhan D, Munshi N, Treon SP, Maxwell C, Pilarski L, Hideshima T, Hoffman RM, Anderson KC. Fluorescence imaging of multiple myeloma cells in a clinically relevant SCID/NOD in vivo model: biologic and clinical implications. Cancer Res 2003;63:6689-96.
- Davies FE, Dring AM, Li C, Rawstron AC, Shammas MA, O'Connor SM, Fenton JA, Hideshima T, Chauhan D, Tai IT, Robinson E, Auclair D, Rees K, Gonzalez D, Ashcroft AJ, Dasgupta R, Mitsiades C, Mitsiades N, Chen LB, Wong WH, Munshi NC, Morgan GJ, Anderson KC. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis.
- Richardson P, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A multicenter phase II multicenter study of bortezomib in patients with relapsed and refractory multiple myeloma. N Engl J Med 2003;348:2609-17.
- Tassone P, Goldmacher V, Neri P, Gozzini A, Shammas MA, Whiteman KR, Hylander L, Carrasco DR, Hideshima T, Shringarpure R, Shi J, Allam CK, Wijdenes J, Venuta S, Munshi N, Anderson KC. Cytotoxic activity of the maytansinoid immunoconjugate B-B4-DM1 against CD138+ multiple myeloma cells. Blood 2004;104:3688-96.
- Munshi N, Hideshima T, Carrasco R, Shammas MA, Auclair D, Davies F, Mitsiades N, Mitsiades C, Kim R, Li C, Rajkumar SV, Fonseca R, Bergsagel L, Chauhan D, Anderson KC. Identification of genes modulated in multiple myeloma using genetically identical twin samples. Blood 2004;103:1799-806.
- Hideshima T, Podar K, Chauhan D, Ishitsuka K, Mitsiades C, Tai YT, Hamasaki M, Schreiner G, Ngyuen AN, Navas T, Munshi NC, Richardson PG, Higgins LS, Anderson KC. p38MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells. Oncogene 2004;23:8766-76.
- Mitsiades CS, Mitsiades NS, MuMullan CJ, Poulaki V, Shringarpure R, Hideshima T, Akiyama M, Chauhan D, Munshi N, Gu X, Bailey C, Joseph M, Libermann TA, Richon VM, Marks PA, Anderson KC. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci U S A 2004;101540-5.
- Anderson KC, Pazdur R, Farrell AT. Development of effective new treatments for multiple myeloma. J Clin Oncol 2005;28:7207-11.
- Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau J, Yehuda DB, Lonial S, Goldschmidt H, Reece D, San Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton W, Boral A, Esseltine DL, Porter JB, Schenkein D, Anderson KC. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487-98.
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