Targeted Therapies Need Targets: HDAC Inhibitors & Targeted Therapies

Genes that regulate cell growth are frequently silenced in cancer cells due to overexpression or improper targeting of chromatin-modifying enzymes. Among these enzymes are HDACs (Table). HDACs are best known for regulating gene expression through the deacetylation of lysine residues found in histones, proteins that are an integral component of the chromatin structure. The acetylation state of histones determines in part whether the chromatin is "open," which means gene expression is allowed, or "closed," meaning gene expression is prohibited. In addition to their effects on the chromatin structure, HDACs also directly and indirectly regulate protein function through deacetylation of key lysine residues found within these proteins.

HDAC Classes

With the approvals of EGFR inhibitors in non-small cell lung cancer, multi-kinase inhibitors such as sorafenib and sunitinib in renal cell cancer, and other targeted therapies, it is evident that these therapies can be effective in prolonging survival and time to progression in a number of cancer indications. However, the responses are primarily partial, and almost all patients develop resistance and progress on their therapy. Combination strategies are considered to be the next step in increasing the number and quality of responses and expanding the benefits of these therapies to additional indications.

Through their ability to regenerate physiological gene expression and protein function in tumor cells, HDAC inhibitors can be viewed as a mechanistically rational choice for combinations with these targeted therapies. Treatment of tumor cells with HDAC inhibitors can have two important effects: 1) to restore the targets that sensitize tumors to the corresponding targeted therapy and 2) downregulate the growth factor pathways that drive primary tumor growth and subsequent resistance to the targeted therapy.

Restoring the Target of EGFR Inhibitors

E-cadherin is a cell-surface protein that associates with EGFR. Loss of E-cadherin is a hallmark of the epithelial-mesenchymal transition (EMT), a process by which the epithelial cell transitions from a normal epithelial histology and acquires more “tumorlike” features (e.g., enhanced migration, loss of cell-cell adhesion properties). Recent work has demonstrated that E-cadherin levels correlate with lung cancer cell sensitivity to EGFR inhibitors, with cells that lack E-cadherin being resistant (more mesenchymal-like) and cells expressing E-cadherin being sensitive (more epithelial-like). E-cadherin expression is in part controlled by a repressor protein complex that typically contains the SNDX-275 targets HDAC 1 combined with HDAC 2 or 3. These HDAC-containing complexes "lock" the promoter governing E-cadherin and prevent its expression.

HDAC inhibition in lung cancer cell lines, using SNDX-275 to inhibit the repressor complex, led to reactivation of E-cadherin and ErbB3 (another protein involved in EGFR signaling) expression. When EGFR inhibitor–resistant cell lines that lack EGFR mutation and gene amplification were treated sequentially with SNDX-275 followed by an EGFR inhibitor, a synergistic effect on growth inhibition and apoptosis was detected. This increase in cell death was similar to what was detected in the EGFR mutant cell line H3255 treated with EGFR inhibitor alone. In this study, SNDX-275 therefore modified the tumor phenotype, leading to restoration of the target for the targeted therapy.¹

Based on these findings, a clinical study of SNDX-275 in combination with erlotinib in non-small-cell lung cancer is currently in progress.

Restoring the Target of Aromatase Inhibitors and Antiestrogens

Estrogen signaling is a key driver of breast cancer cell growth, and targeting this pathway is an effective method of treatment as well as preventive care. There are two isoforms of the estrogen receptor, ERα and ERβ, with ERα mediating the growth properties of breast cancer cells. Aromatase inhibitors function by blocking the production of estrogen in peripheral tissues, resulting in the removal of the proliferative effects of estrogen on breast cancer cells. Despite their improved efficacy compared to tamoxifen, acquired and de novo resistance to AIs is observed.

A variety of resistance mechanisms have been shown to occur in tumor cells resistant to AIs, including epigenetic and growth factor signaling driven loss of ERα expression, activated growth factor signaling pathways, constitutive NFκB activation, estrogen-independent tumor growth, hypersensitivity of tumor cells to low estrogen concentrations, and cyclin D1 over-expression. HDAC inhibitors are one class of compounds that have been shown to inhibit these resistance mechanisms. In preclinical models, treatment of breast cancer cells with SNDX-275 increases ERα and aromatase levels and restores sensitivity of cells to the aromatase inhibitor as well as other types of anti-estrogen therapies such as tamoxifen. In this study, SNDX-275 thus restored the target of therapy and responsiveness to hormonal treatment.²

Based on these data, clinical studies of SNDX-275 in combination with an aromatase inhibitor for the treatment of breast cancer are part of our program.

¹ Witta SE, Gemmill RM, Hirsch FR, et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res. 2006;66(2):944-950.

² Sabnis GJ, Gediya LK, Njar VCO, Brodie AMH. HDAC inhibitors sensitize ER negative breast cancer cells to AIs. Paper presented at: 30th Annual Meeting of the San Antonio Breast Cancer Symposium; December 13 - 16, 2007; San Antonio, TX. Abstract # 2096.