Combinations Overcome Acquired Resistance to BRAF Inhibition
Greger et al. Page 909
BRAF inhibitors have shown clinical benefit; however, resistance eventually occurs. To identify determinants of resistance and new treatments, Greger and colleagues isolated dabrafenib-resistant BRAF mutant melanoma clones and found that NRAS or MEK1 mutations contribute to BRAF inhibitor resistance. Treatment with dabrafenib and the MEK inhibitor trametinib inhibited proliferation and decreased MEK-ERK signaling of these clones. In addition, the resistant clones responded to the combination of a PI3K/mTOR inhibitor with dabrafenib or trametinib. Clinical trials are in progress to evaluate the genetic mutations and test combinations in patients that progress after BRAF inhibitor treatment and in BRAF inhibitor treatment of naive patients.
A Melanoma-Specific Mutation Panel
Dutton-Regester et al. Page 888
Significant success with molecular-based targeted drugs has recently been achieved in metastatic melanoma; however, the success of these drugs is dependent on the presence or absence of mutations within the patient's tumor that can confer drug efficacy or resistance. For this reason, Dutton-Regester and colleagues have developed a high-throughput, sensitive, cost-effective mutation panel for the identification of frequently occurring and clinically relevant mutations in melanoma. When used in a clinical setting, this panel may rapidly and accurately identify potentially effective treatment strategies using novel or existing molecular-based targeted drugs.
CEP-32496, Potent and Efficacious BRAF Inhibitor
James et al. Page 930
CEP-32496, a functionally selective BRAF inhibitor, exhibits selective cytotoxicity for BRAFV600E versus wildtype cells and is bioavailable and active against BRAFv600E xenografts in mice. James and colleagues describe that while like clinically tested BRAF inhibitors CEP-32496 did not inhibit cellular CRAF, it targets other kinases of interest and did not cause hyperplasia with repeat high-dose administration in nonclinical species. The balance of kinase inhibition and tolerability makes CEP-32496 an important new clinical tool, as these properties promise to both provide multiple routes of pathway inhibition and to mitigate against hyperplastic side effects previously observed with selective BRAF inhibitors.
HGF Nanobody Therapy in Nude Mice
Vosjan et al. Page 1017
Hepatocyte growth factor (HGF) is associated with tumor aggressiveness and poor prognosis. We report the development of therapeutic anti-HGF Nanobodies and their potential for PET imaging of HGF expression. Nanobodies radiolabeled with the PET isotope zirconium-89 showed selective tumor targeting in xenograft-bearing mice. In a therapy study using repeated doses of 10, 30 or 100 μg/mouse, all Nanobody-treated mice showed tumor growth delay compared to the control group. In the 100 μg group, 4 out of 6 mice were cured. These results show that HGF Nanobodies have potential for therapy and for assessment of HGF expressing with PET.
- ©2012 American Association for Cancer Research.
Volume 11, Issue 4
