Novel Agents in the Fight Against Melanoma
BRAF inhibitors - The BRAF gene is known to play a part in cell growth, and mutations in BRAF are common in several types of cancer including colon cancer, lung cancer, papillary thyroid cancer, melanoma, billiary cancers and prostate cancers. Approximately half of all melanomas carry a specific BRAF mutation known as V600. Clinical trials of melanoma patients harboring an activating BRAF mutation have shown that treatment with investigational BRAF inhibitors, including vemurafenib (previously PLX4032, Plexxikon/Roche) and dabrafenib (previously GSK2118436, GlaxoSmithKline) results in high initial tumor response rates. Recently, BRAF inhibition has shown survival advantage in metastatic melanoma.
GDC-0449 is a synthetic Hedgehog Pathway Inhibitor meaning that it blocks signals in the Hedgehog Pathway that is known to play a role in tumor growth. Specifically GDC-0449 hinders the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and thus restrains Hedgehog signaling. Use of this drug in Metastatic and Advanced Basal Cell Cancers has led to dramatic regression and tumor control.
Ipilimumab(Yervoy) - is another targeted therapy for cancer, but represents a new class of drug, known as a targeted T cell antibody. Ipilimumab is directed against an antigen on the surface of T cells. The antigen, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), acts as a brake on the T cell. By blocking the brake, the T cell goes into attack mode and kills cancer cells.
MEK inhibition - MEK, also known as mitogen activated protein kinase kinase (MAPKK), is a key component of the RAS/RAF/MEK/ERK pathway, which is frequently activated in human tumors. Inappropriate activation of the MEK/ERK pathway promotes cell growth in the absence of exogenous growth factors.
MLN4924 - MLN4924, is a potent and selective inhibitor of NEDD8-activating enzyme (NAE). MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to cell death in human tumor cells. NAE is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways.
MORAb-004 is a humanized monoclonal antibody specific for endosialin/TEM-1 protein. TEM-1 is expressed on the cell surface of cells called pericytes that are part of the tumor blood vessel architecture, as well as on fibroblast cells that are part of the tumor stroma. TEM-1 is a novel anticancer target expressed in many human malignancies and critical to tumor development and is involved in the development of tumor vasculature. MOR4 is a humanized IgG monoclonal antibody and is the first agent to target TEM-1. It has antitumor activity in a variety of tumors.
NRAS inhibitors - Oncogenic NRAS mutations are frequent in malignant melanoma; comprising 20% of melanomas. This subgroup of patients are distinct from the 50% of melanomas harboring the braf mutation. NRAS mutations were significantly related to melanomas on chronically sun-damaged skin. NRAS- and BRAF-mutated melanomas are biologically distinct therefore it is believed that inhibition of this patway can lead to clinical patient benefit.
Ontak - Ontak is a recombinant DNA-derived cell toxic protein composed of the amino acid sequences for diphtheria toxin followed by the sequences for interleukin-2. It is designed to carry the cytocidal diphtheria toxin to cells that express the IL-2 receptor on their surfaces. The drug binds to the CD25 segment of the receptor; once the toxin fragments enter the cell, death occurs within hours. It is hypothesized that denileukin diftitox could selectively deplete Tregs in melanoma patients and enable the patients' CD8+ T cells to recognize and attack their cancer cells in a better fashion.
PD1/PD-L1 inhibition – Inhibition of antitumor T cell responses can be mediated by the productive interaction between the programmed death-1 (PD-1) receptor on T cells and its ligand PD-L1 D-L1 binds to PD-1 on activated T cells to induce and maintain peripheral tolerance. By blocking this interaction, there is the ability to initiate anti-tumor response similar to the way CTLA-4 inhibitors (Yervoy) work.
MORAb-004 is a humanized monoclonal antibody specific for endosialin/TEM-1 protein. TEM-1 is expressed on the cell surface of cells called pericytes that are part of the tumor blood vessel architecture, as well as on fibroblast cells that are part of the tumor stroma. TEM-1 is a novel anticancer target expressed in many human malignancies and critical to tumor development and is involved in the development of tumor vasculature. MOR4 is a humanized IgG monoclonal antibody and is the first agent to target TEM-1. It has antitumor activity in a variety of tumors.
To learn more about participating in melanoma and skin cancer clinical trials at The Angeles Clinic and Research Institute, call (310) 231-2185 or email: melanoma@theangelesclinic.org.
