There is a growing body of evidence that epigenetic alterations play a pivotal role in a wide variety of cancers. Epigenetic alterations are changes in gene expression that are independent of changes to the underlying DNA sequence. In other words, genetic mutations change gene sequence while epigenetic changes impact gene expression.
What does gene expression have to do with cancer? Normal gene expression ensures that tumor promoter genes are properly silenced and that tumor suppressor genes are properly active, or expressed. These epigenetic pathways are like master switches that regulate gene expression, and are critical for maintaining normal biological function.
One type of epigenetic “switch” is through DNA acetylation and deacetylation – the addition or removal of acetyl chemical groups to DNA. Abnormal acetylation patterns in DNA can lead to improper epigenetic regulation of oncogenes and tumor suppressor genes, leading to tumor growth, proliferation and potentially metastasis.
A proper balance of acetylation and deacetylation is regulated by histone acetyltransferases (HAT) and histone deacetylases (HDACs) enzymes. HAT and HDAC enzymes act together in opposing roles to regulate the expression of other important genes involved in cell growth, survival and differentiation. HAT enzymes function as epigenetic “writers” by adding acetyl groups to key histone and non-histone proteins, while HDACs have an opposing function as epigenetic “erasers” by removing acetyl groups.
Use of HDAC Inhibitors with Other Epigenetic Agents
Combination therapies are an integral part of cancer treatment. The combination of mocetinostat (MGCD103) with agents that target other epigenetic pathways has a strong scientific rationale. The strength of the rationale is based on the crosstalk between epigenetic regulatory molecules which are critical to the regulation of cellular gene expression and the dysregulation of epigenetic pathways that results in tumor progression. Mirati is exploring combinations of mocetinostat with other epigenetic agents (e.g., LSD1 and KDM) as a potential next step in the mocetinostat development program.
Use of HDAC Inhibitors with Other Epigenetic or Immuno-Oncology Agents
Mirati is also assessing combinations of mocetinostat with agents that target immune checkpoints, as there is growing evidence that HDACs may be able to increase the target population, and enhance the activity of immune checkpoint inhibitors. Initial preclinical data suggests that mocetinostat, a Class I-selective HDAC inhibitor, may enhance the anti-tumor activity of checkpoint inhibitor antibodies (anti-programmed cell death ligand (PD-L1) and anti-programmed cell death (anti-PD-1) inhibitors) by increasing tumor cell immunogenicity and decreasing cell types that limit the T-cell mediated tumor immune response. In addition, evidence suggests that mocetinostat enhances tumor cell immunogenicity by selectively inhibiting Class I HDACs, which results in increased human leukocyte antigen (HLA) expression, can increase PD-L1 expression, and decrease immunosuppressive myeloid derived suppressor cells and T regulatory cells. Lastly, in contrast to other HDAC inhibitors, mocetinostat does not inhibit Class II HDACs which may limit the efficacy of immunotherapy and are associated with significant side effects. These data indicate that mocetinostat could be used to enhance the efficacy of immune checkpoint inhibitors, such as PD-1 or PD-L1 antagonists.
MOCETINOSTAT IN COMBINATION WITH IMMUNOTHERAPY
Non-Small Cell Lung Cancer (NSCLC)
The overall five year survival rate for patients with NSCLC is only 16.8% and NSCLC results in the greatest number of cancer deaths in the United States. Over recent years, new therapies have been approved that target gene pathways implicated in progression of NSCLC, including EGFR kinase inhibitors, EML4-ALK inhibitors, and immune checkpoint inhibitors. However, these targets represent only a fraction of the growing list of cancer genes that play a role in NSCLC. There remains a significant unmet medical need to develop new therapies that inhibit multiple targets, particularly those that also inhibit novel targets for which no therapy exists. Backed by a strong scientific rationale, we believe that mocetinostat, combined with immune checkpoint inhibitors (PD-1 or PD-L1 monoclonal antibodies), may result in synergistic immune enhancing anti-tumor effect.