The post-genomic era has provided unprecedented opportunity to examine the complex role of aberrant gene regulation in the development and progression of cancer. Where we once believe all tumors were of a clonal origin that followed a single primary tumorigenic pathway, we are now faced with devising strategies to treat heterogeneous populations of cancer cells within tumors and between metastatic foci. Thus, when tumors are not cured through surgery, radiation or other primary modes of therapy, identifying the primary genetic drivers of growth often provides the best targets for systemic treatment.
The goal of our work is to gain a better understanding of the molecular and cellular abnormalities that lead to progression and spread of medullary thyroid carcinoma (MTC). We believe that a clearer understanding of these processes will translate into advancements in targeted treatment and the monitoring responses to therapy.
RET proto-oncogene – a primary driver of MTC tumorigenesis
Inherited cancer syndromes have played a fundamental role in our understanding of tumorigenesis. For MTC, germline mutations leading to aberrant activation of the RET receptor tyrosine kinase are associated with high penetrance of cancer development. The ability to pharmacologically replace thyroid function allows for its prophylactic removal to prevent the development and spread of cancer. Indeed, the establishment of genotype-phenotype correlations has led to a remarkable reduction in the morbidity associated with this cancer. However, as the spectrum of genetic alterations has expanded it has become increasingly difficult to determine the optimal time of surgical intervention in a cancer-free patient. These same RET mutations also drive sporadic MTC. Our laboratory has worked collaboratively with several investigators to specifically define the presence of germline and somatic RET mutations in an effort to assess their clinical correlates.
RET as a Therapeutic Target
The defining of RET as a critical driver of MTC tumorigenesis led to testing if it also served as a therapeutic target. Our laboratory participated in the early studies that demonstrated that inhibition of RET activity was associated with inhibition of MTC tumor cell growth. The department of endocrine neoplasia and hormonal disorders were part of the international clinical trials that led the FDA approval of 2 drugs, vandetanib and cabozantinib, specifically for the treatment of patients with progressing metastatic MTC. Unfortunately, not all patients respond to these treatments and resistance inevitably develops. For this reason our laboratory has continued to work on uncovering other therapeutic approaches, including additional pathway targets that can be used augment the response to RET-targeted approaches.
The use of Mutant DNA to Monitor MTC Progression
A recent goal in the laboratory is to develop circulating biomarker tests that can be used to define tumor mutation profiles as well as monitor tumor progression. Because thyroidectomy is the primary treatment for MTC tumor tissue is frequently available for genetic and molecular analysis. Genetic analysis of these primary tumors has defined RET and RAS activation as the primary defects found. Recent studies suggest that the presence of these mutations may predict response to systemic treatment. Because of the clear heterogeneity that exist is in all tumors, we have questioned if mutation analysis of the primary tumor best reflects active disease. In order to test this hypothesis we have developed assays to monitor mutated RET DNA in the circulation of patients with MTC. Our goal is to determine if these assays can be used to confirm RET-mediated tumorigenesis, and further ask if quantitative use of circulating mutant DNA can be used as a surrogate for measurement of tumor burden. Long-term we hope to be able to establish a panel of assays that could be used to aid in the personalization of treatment.
Tumor-Initiating Cells – A Pathway to Recurrence and Metastatasis
There is an increasing body of evidence that suggests for some tumor types recurrence and metastasis are mediated through a small subpopulation referred to as tumor-initiating cells or cancer stem cells. Work in our laboratory define the presents of a small CD133+ group of cells in MTC cell lines and patient tumor samples that retain many of the properties associated with tumor-initiating cells. These cells are often resistant to standard treatment approaches and are thought to lay dormant until some stimulus triggers their growth and propagation down a tumor-producing pathway. We, like others, believe that this cell population requires unique the therapeutic targeting in order to elicit true treatment cures. Our laboratory is engaged in molecular analysis of patient-derived tumor-initiating cells in an effort to uncover potential therapeutic targets. In parallel we are examining combinatorial treatments using defined cancer stem cell drugs with those known to target activated RET.