Carmelo Nucera, MD, PhD
Dual targeting of BRAF V600E–positive papillary thyroid carcinoma (PTC) with the anti-BRAF V600E
agent vemurafenib (Zelboraf) and the angiogenesis inhibitor sorafenib (Nexavar) showed promising clinical activity, according to research presented at the 2015 International Thyroid Congress.
Sorafenib was approved in 2013 for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma refractory to radioactive iodine treatment. Antitumor activity with vemurafenib in BRAF
V600E–positive PTC was previously demonstrated in a phase II study presented at the 2013 European Cancer Congress. In the study, the median progression-free survival in treatment-naïve patients who received vemurafenib was 15.6 months.
Carmelo Nucera, MD, PhD, assistant professor at Harvard Medical School, and colleagues used cell cultures of human metastatic/recurrent BRAF V600E
-PTCs and tested the effects of vemurafenib versus sorafenib used as single agents or in combination. To date, they have used predominately three types of assays. These include biochemical assays of enzyme activity along with two dynamic cellular assays—measures of cell-cycle proliferation and in vitro microenvironmental analysis: migration and motility.
Nucera pointed out that BRAF V600E
PTCs responded to vemurafenib than sorafenib. In contrast, with wild-type BRAF
cells, the BRAF inhibitor does not work and sorafenib works very well. Ultimately the combination overlaps in activity, Nucera said.
The key, according to Nucera, is tumor heterogeneity, and therefore, the tumor microenvironment needs to be considered. Macrophages, for example, are an important component in the anaplastic pericyte microenvironment. Macrophages and endothelial cells exist in this microenvironment.
Nucera’s group 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.
Higher PDGFR-β was observed by Nucera et al in BRAF V600E cells 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 sorafenib 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 a pan¬–tyrosine kinase inhibitor (TKI) like sorafenib, you can improve the activity to kill any tumor cell, said 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, combining the BRAF inhibition with a pan-TKI will fundamentally work on any tumor cell.
Sisms J, Antonello Z, Nucera C, et al. Combinatorial targeting with anti-BRAFV600E and anti-angiogenesis therapy enhances cell death and suppresses cell migration in metastatic papillary thyroid carcinoma. Presented at: 2015 International Thyroid Congress; October 18-23, 2015; Orlando, FL. Abstract 106.
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