Anti-BRAF V600E Plus Antiangiogenesis May Possess Greater Activity Against Metastatic Papillary Thyroid Carcinoma

Harvard

Carmelo Nucera, MD, PhD

BRAF V600Eis essential to the survival of many tumors. Accordingly,BRAF V600Ehas been the focus of targeted therapeutics like the BRAF V600E-selective inhibitor, vemurafenib, which has been used for papillary thyroid carcinomas (PTCs).

While BRAF V600E and angiogenesis inhibitors are frequently used, a lack of response has been observed in many human cancer cells. At the 15th International Thyroid Congress, Carmelo Nucera, MD, PhD, assistant professor at Harvard Medical School presented data from his studies that explored how the combination of antiangiogenesis/tyrosine kinase inhibitors (TKIs) may impact known BRAF inhibitors.

Nucera et al used cell cultures of human metastatic/recurrentBRAF V600E-PTCs and tested the effects of vemurafenib (selective inhibitor ofBRAF V600E) versus sorafenib (antiangiogenesis/TKI) used as single agents or in combination. To date, they have used predominately three types of assays. This includes biochemical assays of enzyme activity along with two dynamic cellular assays, such as measures of cell-cycle proliferation and in vitro microenvironmental analysis: migration and motility.

Nucera pointed out thatBRAF V600E-PTCs responded to the BRAF inhibitor vemurafenib more than to the TKI sorafenib. By contrast, if you use wild-type BRAF cells, then the BRAF inhibitor does not work and sorafenib works very well. Ultimately the combination overlaps in activity, according to Nucera.

Nucera states that it is all about tumor heterogeneity, therefore, the tumor microenvironment needs to be considered. Macrophages, for example, are an important component in the anaplastic pericyte microenvironment. We know that macrophages and endothelial cells exist in this microenvironment.

Nucera’s group has observed that the pericytes act like stem cells, interacting with endothelial cells to regulate angiogenesis. Pericytes spread after exposure to various signaling molecules like PDGFR-β, according to Nucera. Pericytes have a strong capability to produce an extracellular matrix, which may ultimately confer advantage to PTC cells to promote their migration and invasion.

The researchers observed higher PDGFR-β inBRAF V600Ecells than in the wild-type equivalent, but addition of a BRAF inhibitor caused down-regulation of PDGFR-β activation. No response was seen after sorafenib treatment, while the combination belies the treatment of the single sorafenib agent.

Nucera’s study preliminarily suggests that the combination of an antiangiogenic compound and a BRAF inhibitor may be more effective than either agent alone, not only in blocking the proliferation of PTC cells, but also in preventing cell types like pericytes in the microenvironment from promoting otherwise reproductive advantages to PTC cells.

Nucera highlighted that these results indicate for the first time that PTC cells express VEGFR2, and this dual combination treatment with anti-BRAF V600E and antiangiogenesis therapy is likely to improve therapeutic response in metastatic BRAF V600E-positive PTC cells by directly reducing cell survival and migratory capacities via pERK1/2 and pPDGFR-β down-regulation.

Richard Kloos, MD, cochair for the session and professor of medicine at Ohio State University, stated that the value of adding vemurafenib must be that the BRAF activity is not strong enough. Kloos then asked whether or not the sorafenib effect is really a dose effect working through BRAF. Nucera elaborated that the BRAF inhibitor is working on the BRAF system. Therefore, if you use pan tyrosine kinase inhibitor like sorafenib, you can improve the activity to kill any tumor cell, according to Nucera. The rationale for using an antiangiogenic agent is that you have a human system with many different cells with many different TK targets. In Nucera’s observations the BRAF inhibition with a pan TKI will fundamentally work on any tumor cell.

Nucera C. Combinatorial targeting with anti-BRAFV600E and anti-angiogenesis therapy enhances cell death and suppresses cell migration in metastatic papillary thyroid carcinoma. Presented at the 15th International Thyroid Congress: Lake Buena Vista, Florida; October 20, 2015. Abstract #106.