- PROFESSOR Medicine, Hematology and Medical Oncology
American Board of Internal Medicine
MD, UMDNJ - University Hospital
Residency, Internal Medicine
Brigham and Women's Hospital, Harvard Medical School
Fellowship, Hematology & Onc.
Brigham and Women's Hospital, Harvard Medical School
Randall F. Holcombe, MD is Chief Medical Officer, Cancer,
Mount Sinai Health System; Professor of Medicine, Division of Hematology and Medical Oncology and Director of Clinical Cancer Affairs for Mount Sinai Medical Center. He has extensive experience in the conduct of clinical trials and is involved directly in clinical care and research for patients with colorectal cancer and other GI malignancies. Dr. Holcombe also serves as Director of the Ruttenberg Treatment Center at Mt. Sinai Hospital, Director of GI Medical Oncology and Deputy Director for the Tisch Cancer Institute.
A leading authority in colon cancer, Dr. Holcombe has broad experience ranging from basic science and translational research to clinical trials and patient care. His research initially focused on levamisole, an adjuvant treatment for people with stage III colon cancer, which led to a national clinical trial. His focus since 1997 has been on the signaling of a protein called Wnt and its role in colon cancer development and progression. He has served as the principal investigator on 127 clinical trials, and led the team that was the first to describe the selective expression of the LEF1 gene in colon cancer. Most recently, his laboratory has begun examining the clinical effects of a naturally-derived compound called resveratrol on the prevention or treatment of colon cancer. He is deeply involved in the promotion and facilitation of translational and clinical research. His research has been funded by the NIH and multiple foundations and has resulted in more than 90 peer-reviewed manuscript publications and more than 140 published conference abstracts.
In the News
Dr. Holcombe discusses treatment of colon cancer in The Daily News feature The Daily Check Up.
1. Byun T, Karimi M, Marsh JL, Milovanovic T, Lin F, Holcombe RF. Expression of secreted Wnt antagonists in gastrointestinal tissues: Potential role in stem cell homeostasis. J Clinical Pathology 58:515-519, 2005. PMID:15858124. PMCID:PMC1770654
2. Nguyen A, Rosner A, Milovanovic T, Hope C, Planutis K, Saha B, Chaiwun B, Lin F, Imam A, Marsh JL, Holcombe RF. Wnt pathway component LEF1 mediates tumor cell invasion and is expressed in human and murine breast cancers lacking erbB2 (her-2/neu) overexpression. International Journal of Oncology 27:949-956, 2005. PMID:16152310
3. Holcombe RF, McLaren CE, Milovanovic T. Immunomodulation with low dose levamisole in patients with colonic polyps. Cancer Prevention and Detection, 30:94-98, 2006. PMID:16458451
4. Holcombe RF. Who’s watching out for the clinical academician? Academic Medicine 80:905-907, 2005. PMID:16186607
5. Zi X, Guo Y, Simoneau AR, Hope C, Xie J, Holcombe RF, Hoang BH. Expression of Frzb/secreted frizzled-related protein 3, a secreted Wnt antagonist, in human androgen-independent prostate cancer PC-3 cells suppresses tumor growth and cellular invasiveness. Cancer Research 65:9762-9770, 2005. PMID:16266997
6. Choi J, Kong K, Mozzafar T, Holcombe RF. Delayed oxaliplatin-associated neuropathy following adjuvant chemotherapy for stage III colon cancer. Anti-Cancer Drugs, 17:103-105, 2006. PMID:16458451
7. Holcombe RF. Re-engineering the clinical research enterprise: Will the new vision for translational and clinical science be successful without more support for mentors? Journal of Investigative Medicine 54:231-234, 2006. PMID:16984794
8. Guo Y, Zi X, Koontz Z, Kim A, Xie J, Gorlick R, Holcombe RF, Hoang BH. Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma SAOS-2 cells. J Orthopaedic Research, 25:964-971, 2007 [Feb 22, Epub ahead of print]. PMID:17318900
9. Planutis K, Planutiene M, Moyer MP, Nguyen A, Perez C, Holcombe RF. Regulation of norrin receptor frizzled 4 by Wnt2 in colon-derived cells: Evidence for cross-talk between colon cancer and normal colonic mucosa. BMC Cell Biology 8:12-21, 2007. PMID:17386109. PMCID:PMC1847812
10. You XJ, Bryant PJ, Jurnak F, Holcombe RF. Expression of Wnt pathway components frizzled and disheveled in colon cancer arising in patients with inflammatory bowel disease. Oncology Reports 18:691-694, 2007. PMID:17671721
11. Zell JA, McEligot AJ, Ziogas A, Holcombe RF, Anton-Culver H. Differential effects of wine consumption on colorectal cancer outcomes based on family history of the disease. Nutrition and Cancer: An International Journal 59:36-45, 2007. (co-senior author) PMID:17927500 [Co-Senior Author on this manuscript.]
12. You XJ, Nguyen AV, Albers G, Lin F, Holcombe RF. Wnt pathway-related gene expression in inflammatory bowel disease. Digestive Diseases & Sciences 53:1013-1019, 2008. [October 16, 2007 - Epub ahead of print]. PMID:17939044
13. Gatcliffe TA, Monk BJ, Planutis, K, Holcombe RF. Wnt signaling in ovarian tumorigenesis. International J Gynecol Cancer 18:954-962, 2008. [November 6, 2007 - Epub ahead of print]. PMID:17986238. PMCID: PMC2575063.
14. Chang KJ, Lee JG, Holcombe RF, Kuo J, Muthusamy M, Wu M. Endoscopic ultrasound delivery of an anti-tumor agent to treat a case of pancreatic cancer. Nature Clinical Practice: Gastroenterology & Hepatology, 5:107-111, 2008. PMID:18253139
15. Hope C, Planutis K, Planoutiene M, Moyer MP, Johal KS, Woo J, Santoso C, Hanson JA, Holcombe RF. Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: Implications for colon cancer prevention. Molecular Nutrition and Food Research 52 Suppl 1:S52-61, 2008. PMID: 18504708. PMCID: PMC2519107
16. Ehsanipoor RM, Rajan P, Holcombe RF, Wing DA. Limitations of ADAMTS-13 activity level in diagnosing thrombotic thrombocytopenic purpura in pregnancy. Clinical and Applied Thrombosis/Hemostasis 2008. [November 19, 2008 – Epub ahead of print]. PMID: 19022799
17. Tang Y, Simoneau AR, Liao W-X, Yi G, Hope C, Liu F, Li S, Xie J, Holcombe RF, Jurnak FA, Mercola D, Hoang BH, Zi X. WIF1, a Wnt pathway inhibitor, regulates SKP2 and c-myc expression leading to G1 arrest and growth inhibition of human invasive urinary bladder cancer cells. Molecular Cancer Therapeutics 8:458-468, 2009. [January 27, 2009 – Epub ahead of print]. PMID: 19174556. PMCID: PMC2768341.
18. Nguyen AV, Martinez M, Stamos MJ, Moyer MP, Planutis K, Hope C, Holcombe RF. Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on Wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Management & Research 1:25-37, 2009.
19. Kay JY, Pitts B, Holcombe RF. Building an Office of Clinical Research and Trials: The UC Irvine Experience. J Clinical Research Best Practices 5(3):1-7, 2009 (March).
20. Najdi R, Syed A, Arce L, Theisen H, Ting J-H, Atcha F, Nguyen AV, Martinez M, Holcombe RF, Edwards RA, Marsh JL, Waterman ML. Wnt-directed changes in nuclear export and gene expression alter TCF function in colon cancer. Oncogene 28:4133-46, 2009. [September 14, 2009 - Epub ahead of print]. PMID: 19749792. PMCID: PMC2787979.
21. Holcombe RF, Hollinger KJ. Establishing a rational mission-focused, productivity-based model for sustainable support of academic Hematology/Oncology faculty and divisions. Journal of Oncology Practice 6:74-79, 2010. [Editorial/Commentary: Hennessy J. Observations on the University of California at Irvine Experience: Common Ground with Community Practices. Journal of Oncology Practice 6:79-80, 2010.]
22. Nguyen AV, Albers CG, Holcombe RF. Differentiation of tubular and villous adenomas based on Wnt pathway-related gene expression profiles. International Journal Molecular Medicine 26:121-125, 2010. PMID: 20514431.
Best Doctors in America: 2005-2010; 2011-2015
“Teacher of the Year”, UCIrvine Hematology/Oncology Fellowship Program - 2009
Physician of Excellence, Orange County Medical Association, 2006-2010
Dr Holcombe's Research Interests
1. Colon cancer prevention: Colon cancer is the third leading cause of cancer death for both men and women in the United States. Preventing this disease through the development of novel agents, many of them derived from naturally occurring compounds, is an area of specific interest. These compounds are undergoing testing both in the laboratory and in pilot clinical trials.
2. Cancer Immunology: The immune system plays a critical role in both the prevention and response to cancer. Understanding the immune response to cancer, and the immunologic abnormalities induced by the cancer itself and the associated treatments, is a major focus of the laboratory.
3. Wnt Signaling in Cancer: The Wnt signal transduction pathway is critical for the development and progression of many cancers but colon cancer in particular. Laboratory research is ongoing which will define the role of specific components of the Wnt signaling pathway in colon cancer and define mechanisms by which activation of this pathway contributes to a malignant phenotype. These studies are performed with an eye toward the development of new diagnostic tests, validation of new prognostic markers, and implementation and testing of novel targeted therapeutic interventions.
4. Integrative Oncology: Natural compounds such as resveratrol may have activity for both the treatment and prevention of cancer. Laboratory research is ongoing to define the mechanism of action of this compound. Active clinical studies in patients with cancer may provide additional information regarding efficacy.
5. Clinical and Translational Research: Dr. Holcombe’s major focus has been on the development of hypothesis-driven, investigator-initiated trials in the area of gastrointestinal malignancies. Currently, Dr. Holcombe has several clinical trials in development for the treatment of patients with colon cancer, including one supported by an NIH R21 grant for which he holds an IND from the FDA.
Holcombe RF, Hollinger KJ. Establishing a rational mission-focused, productivity-based model for sustainable support of academic Hematology/Oncology faculty and divisions. . Journal of Oncology Practice 2010; 6: 74-79.
Nguyen AV, Albers CG, Holcombe RF. Differentiation of tubular and villous adenomas based on Wnt pathway-related gene expression profiles. International journal of molecular medicine 2010 Jul; 26(1).
Najdi R, Holcombe RF, Waterman ML. Wnt signaling and colon carcinogenesis: beyond APC. Journal of carcinogenesis 2011; 10.
Iqbal S, Rankin C, Lenz HJ, Gold PJ, Ahmad SA, El-Khoueiry AB, Messino MJ, Holcombe RF, Blanke CD. A phase II trial of gemcitabine and capecitabine in patients with unresectable or metastatic gallbladder cancer or cholangiocarcinoma: Southwest Oncology Group study S0202. Cancer chemotherapy and pharmacology 2011 Dec; 68(6).
Abou-Alfa GK, Chan SL, Lin CC, Chiorean EG, Holcombe RF, Mulcahy MF, Carter WD, Patel K, Wilson WR, Melink TJ, Gutheil JC, Tsao CJ. PR-104 plus sorafenib in patients with advanced hepatocellular carcinoma. Cancer chemotherapy and pharmacology 2011 Aug; 68(2).
Planutiene M, Planutis K, Holcombe RF. Lymphoid enhancer-binding factor 1, a representative of vertebrate-specific Lef1/Tcf1 sub-family, is a Wnt-beta-catenin pathway target gene in human endothelial cells which regulates matrix metalloproteinase-2 expression and promotes endothelial cell invasion. Vascular cell 2011; 3.
Martinez M, Ono N, Planutiene M, Planutis K, Nelson EL, Holcombe RF. Granulocyte-macrophage stimulating factor (GM-CSF) increases circulating dendritic cells but does not abrogate suppression of adaptive cellular immunity in patients with metastatic colorectal cancer receiving chemotherapy. Cancer cell international 2012; 12(1).
Alistar A, Sung M, Kim M, Holcombe RF. Clinical pathways for pancreatic neuroendocrine tumors. Journal of gastrointestinal cancer 2012 Dec; 43(4).
Dellinger TH, Planutis K, Jandial DD, Eskander RN, Martinez ME, Zi X, Monk BJ, Holcombe RF. Expression of the Wnt antagonist Dickkopf-3 is associated with prognostic clinicopathologic characteristics and impairs proliferation and invasion in endometrial cancer. Gynecologic oncology 2012 Aug; 126(2).
Dellinger TH, Planutis K, Tewari KS, Holcombe RF. Role of canonical Wnt signaling in endometrial carcinogenesis. Expert review of anticancer therapy 2012 Jan; 12(1).
Alistar A, Kim M, Warner R, Moshier E, Holcombe R. Pancreatic polypeptide secreting tumors: An institutional experience and review of the literature. . J Solid Tumors 2012 August; 2: 11-18.
Pintova S, Sidhu H, Friedlander PA, Holcombe RF. Sweet's syndrome in a patient with metastatic melanoma after ipilimumab therapy. Melanoma research 2013 Dec; 23(6).
Planutis K, Planutiene M, Nguyen AV, Moyer MP, Holcombe RF. Invasive colon cancer, but not non-invasive adenomas induce a gradient effect of Wnt pathway receptor frizzled 1 (Fz1) expression in the tumor microenvironment. Journal of translational medicine 2013; 11.
Adelson KB, Qiu YC, Evangelista M, Spencer-Cisek P, Whipple C, Holcombe RF. Implementation of electronic chemotherapy ordering: an opportunity to improve evidence-based oncology care. Journal of oncology practice / American Society of Clinical Oncology 2014 Mar; 10(2).
Holcombe RF. Cancer clinical research: return on investment in the era of value-based purchasing. Journal of oncology practice / American Society of Clinical Oncology 2014 Sep; 10(5).
Planutis K, Planutiene M, Holcombe RF. A novel signaling pathway regulates colon cancer angiogenesis through Norrin. Scientific reports 2014; 4.
Galsky MD, Posner M, Holcombe RF, Lee KM, Misiukiewicz K, Tsao CK, Godbold J, Soto R, Gimpel-Tetra K, Lowe N, Oh WK. Phase Ib study of dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin in patients with advanced solid tumors. Cancer chemotherapy and pharmacology 2014 Sep; 74(3).
- A Phase 1 Study of Ly2801653 in Patients with Advanced Cancer
- A feasibility and adherence study of personalized therapeutic interventions targeting minimal residual disease following adjuvant colon cancer therapy
- Genistein Combined with FOLFOX or FOLFOX-Avastin for treatment of Metastatic Colorectal Cancer: Phase I/II Pilot Study
- A phase 2 randomized multicenter study of PEGPH20 (hyaluronidase) combined with nab-paclitaxel plus gemcitabine compared with nab-paclitaxel plus gemcitabine in subjects with stage IV previously untreated pancreatic cancer
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Dr. Holcombe did not report having any of the following types of financial relationships with industry during 2014 and/or 2015: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
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