Dr. Holcombe has four primary research areas:

1. Health services and cancer care delivery research in oncology Health Services and quality-focused research, including a description of a novel compensation model for clinical oncologists, development of a new tool to monitor adherence to evidence-based guidelines and proposal of a new paradigm for consideration of healthcare quality. Additional research studies have focused on patient-reported outcomes, and specifically on the influence of demographic and structural factors that non-variably affect patient satisfaction scores, a critical element in value-based reimbursement models. Interventions to measure and improve care coordination for cancer patients have been implemented and evaluations as to how clinical trials may positively contribute to patient outcomes have been undertaken. These studies advance the field of health services research both for oncology and for healthcare overall and many have had a specific focus on rural populations.

2. Oncology Clinical Investigations as a practicing medical oncologist and holding positions of oversight of cancer clinical trials over the past 20 years, Dr. Holcombe has been involved in numerous National Cancer Institute (NCI) cooperative group, industry and investigator-initiated trials. Many studies have been translational in nature, including those involving natural products. He has also conducted additional behavioral and health sciences clinical research studies, both investigator-initiated and sponsored by the cancer care delivery component of the National Community Oncology Research Program. This work contributes to the base of knowledge that serves ultimately to reduce the burden of cancer for patients.

3. Wnt signaling in colon cancer efforts have focused on identifying key Wnt pathway components that are dysregulated in colon cancer and the mechanisms by which Wnt signaling in the tumor microenvironment promotes invasion and metastases. Dr. Holcombe's group described the selective expression of LEF1 in colon cancer and a novel Wnt-dependent pathway that controls the distribution of specific TCF isoforms. They also identified a novel Wnt-stimulating ligand, Norrin that may control angiogenesis in the colon tumor microenvironment. These studies have advanced the understanding of Wnt signaling as a highly regulated signaling pathway that not only promotes carcinogenesis but also influences tumor invasion and metastases.

4. Role and mechanisms of action of natural products for cancer treatment and prevention research defining the activity of a naturally-derived compound, resveratrol, on Wnt signaling in vitro in colon cancer cells and in vivo in colon cancer and normal colonic mucosa. This has included an investigator-initiated clinical trial of resveratrol and freeze-dried grape powder that demonstrated that the primary effects were on normal mucosa, suggesting that the principal effectiveness may be in cancer prevention, rather than cancer treatment. The group confirmed the activity of a resveratrol-containing whole food in modulation of Wnt signaling in patients, particularly those at increased risk for the development of colon cancer. More recently, the group demonstrated that the soy-derived product genistein inhibits Wnt signaling in colon cancer cells in vitro through different mechanisms and conducted an investigator-initiated therapeutic clinical trial in patients with colon cancer.

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