Christopher D. Collier, MD
Phone: (317) 274-7914
Phone: (317) 944-0920, Patient issues/appointments
550 University Blvd.
Indianapolis, IN 46202
- Assistant Professor of Orthopaedic Surgery, Department of Orthopaedic Surgery, IU School of Medicine
- Edward H. and Yvonne Boseker Scholar in Orthopaedics
- Associate member
Indiana University Melvin and Bren Simon Cancer Center, Tumor Microenvironment and Metastasis
As a clinically-active orthopaedic oncologist, my goal is to develop basic science and translational research strategies to answer critical questions pertaining to the musculoskeletal oncology patient. Specific areas of interest include: (1) predicting the oligometastatic state in metastatic bone disease; (2) evaluating the efficacy and mechanistic basis for epigenetic therapies for osteosarcoma; and (3) exploring the molecular origins of sarcoma. (1) Predicting the oligometastatic state in kidney cancer metastasis to bone The oligometastatic hypothesis proposes that metastasis comprises a spectrum of disease, ranging from a single indolent site to widespread malignancy. Oligometastatic disease by definition is an intermediate clinical state in which metastatic lesions are limited in number and activity. Patients with oligometastatic disease are common, have improved survival compared to those with disseminated disease, and are more likely to benefit from local treatment, including metastectomy. Mounting evidence supports a molecular basis for this spectrum of metastatic virulence, in which clonal populations of cells from the primary tumor obtain variable genetic alterations that determine the metastatic phenotype. Understanding these molecular signatures offers an opportunity to stratify metastatic disease from the time of biopsy to predict survival and guide local treatment. This approach is appealing for the surgical treatment of metastatic bone disease, in particular, which has historically been limited to short-term and palliative stabilization to prevent pathologic fracture. Considering that metastatic cancer patients are now living longer and, in some cases, managing their cancer as a chronic condition, orthopaedic surgeons and others will increasingly need to personalize the management of metastatic bone disease and require new prognostic tools to do so. Metastatic renal cell carcinoma to bone (MRCCB), of which the clear cell subtype (ccMRCCB) makes up the majority of cases, is the most likely clinical scenario to benefit from this approach. As a radioresistant cancer, prophylactic stabilization alone often fails to last the duration of the patient’s life. Additionally, several retrospective studies suggest improved survival after resection of solitary skeletal metastases. Our collaborators recently described an integrated approach that combines clinical risk stratification with molecular subtypes to define a curable oligometastatic state in colorectal liver metastasis. Applying these methods to ccMRCCB may provide a framework to identify patients most likely to benefit from aggressive local therapy. We therefore hypothesize that molecular analysis of ccMRCCB patient samples can predict survival and identify a favorable molecular subtype, resembling an oligometastatic state. (2) Efficacy and mechanistic basis for epigenetic therapies in osteosarcoma Epigenetic deregulation is an emerging hallmark of cancer that enables tumor cells to escape surveillance by tumor suppressors and ultimately progress. The structure of the epigenome consists of covalent modifications of chromatin components, including acetylation by histone acetyltransferases (HATs) and deacetylation by histone deacetylases (HDACs). Targeting these enzymes with inhibitors to restore epigenetic homeostasis has been explored for many cancers. Osteosarcoma, an aggressive bone malignancy that primarily affects children and young adults, is notable for widespread genetic and epigenetic instability. For example, recent whole-genome sequencing suggests that osteosarcomas are driven by a relatively small number of mutations compared to adult tumors – frequently in genes encoding epigenetic regulators – while copy number alterations and structural variants predominate. Epigenetics may also be critical in osteosarcoma metastases, which are accompanied by a shift in the cancer epigenome despite minor changes in the mutational landscape. For these reasons, the emergence of epigenomic therapies has been met with great enthusiasm by those studying osteosarcoma, owing to the relatively limited activity of other newer agents and the significant epigenetic dysregulation observed in osteosarcoma tumors. We recently developed a three-dimensional in vitro osteosarcoma drug-screening platform that provides highly-uniform sarcospheres to mimic micrometastatic disease. Sarcospheres generated from three highly-metastatic human cell lines were then used to screen the NCI panel of 114 FDA-approved oncology drugs. Two of the fifteen most effective drugs were the HDAC inhibitors romidepsin and vorinostat, which were the only two epigenetic therapies included in the panel. After further characterization in normal cell lines and in combination with standard-of-care MAP (methotrexate, doxorubicin, and cisplatin) chemotherapy, romidepsin emerged as the most promising drug evaluated. These findings are consistent with the growing interest in epigenetic therapies for the treatment of osteosarcoma and suggest the need for further preclinical evaluation of the agents to optimize their success in scarcely available clinical trials. Critical to these efforts will be the development of more selective therapies to maximize their effectiveness while minimizing toxicity. This will require a greater understanding of the mechanistic basis for epigenetic therapies in osteosarcoma and their interaction with current standard-of-care MAP therapy. We therefore hypothesize that epigenetic therapies, including the HDAC romidepsin, are promising treatments for osteosarcoma patients and could provide mechanistic insight into the role of epigenetic dysregulation in the pathogenesis of osteosarcoma. (3) Mechanisms of oncogenesis in slowly dividing tissues. Classic oncogenesis, as exemplified by colon adenocarcinoma, follows a step-wise progression from normal tissue to premalignancy and ultimately cancer. This transformation is accomplished over time by the accumulation of sufficient mutations to overwhelm inherent cellular defense mechanisms mediated by tumor suppressors. Mutations are relatively rare events that occur within dividing cells and therefore, it is not surprising that rapidly dividing tissues give rise to the most common cancers in humans. An effort to compare the lifetime number of stem cell divisions for a given tissue of origin to the lifetime risk of developing that cancer demonstrates a clear relationship (Tomasetti, et. al., Science, 2015). However, this relationship is not 1:1 and in fact, a single division of a small intestine stem cell is associated with a 2x10-15 lifetime risk of small intestinal adenocarcinoma compared to a division of a single osteoblast stem cell, which is associated with a 5,000-fold higher lifetime risk of osteosarcoma at 1x10-11. These findings suggest that the development of cancer is insufficiently explained by the number of lifetime cell divisions in the tissue of origin. Decades of cancer research has established clear environmental, hormonal, metabolic, and inherited risk factors for the development of specific cancers. The vast majority of these pressures induce mutation either by direct DNA damage or indirectly through tissue proliferation. If mutation is the ultimate driving force in oncogenesis, then a relatively constant number of mutations would be expected across all cancer types. However, the emergence of next-generation sequencing has showed that this is not true. One possibility is that rapidly dividing tissues have adapted to tolerate mutational stress without malignant transformation. Certain tissue types could therefore be evolutionarily wired to resist oncogenesis by activating epigenetic programs that enhance tumor suppressor activity. Understanding the basis for these observed differences among tissue types could inform therapies to bolster inherent cellular defense mechanisms and render cancer cells more susceptible to traditional cytotoxic chemotherapy. We therefore hypothesize that slowly dividing tissues, in the absence of environmental stressors, are deficient in selective pressures to upregulate tumor suppressor activity controlled by epigenetic pathways. These tissues are therefore more susceptible to catastrophic genetic events and permit the emergence of cancer despite fewer somatic mutations.
Fellowship - University of Chicago, Chicago, IL 07/2020
Residency - Case Western Reserve University, Cleveland, OH 06/2019
Post-doctoral Fellowship - Case Western Reserve University, Cleveland, OH 06/2015
Internship - Case Western Reserve University, Cleveland, OH 06/2014
M.D. - University of Chicago, Chicago, IL 06/2013