Targeting the Epigenome in Ovarian Cancer
Targeting the Epigenome in Ovarian Cancer
HDAC inhibitors exhibit both histone-specific epigenetic effects as well as effects on nonhistone proteins, including, for example, RUNX3, HIF1α, NFκB, p53 and E2F1, among others that are highly relevant to cancer. These nonhistone effects alter protein stability as well as interaction with other proteins and DNA. Thus, therapeutic response is not likely to be entirely due to inhibition of histone deacetylation, but also to the changes in acetylation status of other nonhistone proteins. Improved comprehension of the effects of HDAC inhibitors is required in order to develop the appropriate means to monitor drug response.
A major limitation associated with targeting DNMT enzymes (as well as HDACs) is lack of specificity. It is currently not possible to reactivate only specific target genes through use of DNMT inhibitors therapy. DNMT inhibition disrupts maintenance methylation throughout the genome during DNA replication; as such, the generation of each new daughter cell is associated with progressive losses in genome-wide methylation. Can such nonspecific reversal of DNA methylation have a negative effect on resensitizing tumors to platinum or other DNA damaging agents? For example, platinum compounds induce DNA adduct formation, which triggers cells to undergo apoptosis. Many DNA repair pathway genes are targeted by methylation in cancers, including BRCA1, MGMT, GSTPI and MLH1. Restoration of expression of these genes via DNMT inhibitors treatment could inadvertently lead to enhancement of drug resistance.
Another shortcoming of all current therapeutic approaches used to treat women with epithelial ovarian cancer is that the cancer cells most effectively targeted by these therapies may not be those responsible for causing the disease or its recurrence. The idea that cancer stem cells (cells that possess stem cell-like characteristics, are tumorigenic and able to undergo asymmetric cell division to produce the heterogeneous cell types required to form a tumor) give rise to ovarian cancer is an idea currently receiving much attention. New research is beginning to unveil information regarding the identity and behavior of putative ovarian cancer stem cells. While progress has been made in selecting and characterizing these cells in vitro and in vivo based on cell surface marker expression, and their ability to recapitulate the tumor when passaged in mice, the origin of this cell population(s) is presently unclear. For example, while increasing evidence is pointing to secretory epithelial cells within the fallopian tube fimbriae epithelium as the source of serous ovarian cancer, there are no data available to support that these particular cells represent a normal tissue stem cell, or that these cells can be reprogrammed to adopt a stem cell-like phenotype.
Cancer stem cells are thought to retain phenotypes associated with a normal stem cell population, including a slow rate of growth. Cancer stem cells also express high levels of drug transporter molecules, including those characterized in ovarian cancer, thought to confer resistance to standard chemotherapeutics owing to their ability to efflux these drugs from the cell. If true, the idea that cancer stem cells are responsible for epithelial ovarian cancer has strong implications for disease recurrence. If such a cell population – presumed to be a very small proportion of the overall tumor cell population – is able to survive primary chemotherapy, then it is possible that these cells enter into a state of slow proliferation or dormancy during apparent disease remission. This period of remission can last for months to years, during which the location and niche of this cell population is not known. However, it is clear that something triggers these residual cancer cells to emerge again as recurrent, and often, chemoresistant disease.
Normal stem cells maintain epigenetic plasticity to allow for formation of differentiated progeny; it is conceivable that cancer stem cells also retain epigenetic plasticity, which may make them more vulnerable to epigenetic modulatory drugs (Figure 2). While combined epigenetic therapies with standard chemotherapeutic agents offers the opportunity to reactivate genes required to provoke a response to these drugs, single agent use of epigenetic therapeutics have largely been ineffective. It may be that epigenetic therapies will have utility when administered following completion of treatment using standard chemotherapeutics, as part of maintenance or consolidation therapy during the time when residual cancer cells are entering a state of slow growth or dormancy. In support of the feasibility of this approach, several HDAC inhibitors, including suberic bishydroxamic acid, trichostatin A and sodium butyrate, are effective at causing cell death of both actively proliferating and nonproliferating cells. My laboratory is currently conducting preclinical testing of several drugs that we have shown are more effective than cisplatin or paclitaxel at targeting slow-proliferating ovarian cancer cell populations in vitro. Similarly, Wei et al. have shown that Müllerian inhibiting substance is more effective at targeting ovarian cancer stem cells than standard chemotherapeutic agents.
Current Limitations of Epigenetic Therapy
HDAC inhibitors exhibit both histone-specific epigenetic effects as well as effects on nonhistone proteins, including, for example, RUNX3, HIF1α, NFκB, p53 and E2F1, among others that are highly relevant to cancer. These nonhistone effects alter protein stability as well as interaction with other proteins and DNA. Thus, therapeutic response is not likely to be entirely due to inhibition of histone deacetylation, but also to the changes in acetylation status of other nonhistone proteins. Improved comprehension of the effects of HDAC inhibitors is required in order to develop the appropriate means to monitor drug response.
A major limitation associated with targeting DNMT enzymes (as well as HDACs) is lack of specificity. It is currently not possible to reactivate only specific target genes through use of DNMT inhibitors therapy. DNMT inhibition disrupts maintenance methylation throughout the genome during DNA replication; as such, the generation of each new daughter cell is associated with progressive losses in genome-wide methylation. Can such nonspecific reversal of DNA methylation have a negative effect on resensitizing tumors to platinum or other DNA damaging agents? For example, platinum compounds induce DNA adduct formation, which triggers cells to undergo apoptosis. Many DNA repair pathway genes are targeted by methylation in cancers, including BRCA1, MGMT, GSTPI and MLH1. Restoration of expression of these genes via DNMT inhibitors treatment could inadvertently lead to enhancement of drug resistance.
Another shortcoming of all current therapeutic approaches used to treat women with epithelial ovarian cancer is that the cancer cells most effectively targeted by these therapies may not be those responsible for causing the disease or its recurrence. The idea that cancer stem cells (cells that possess stem cell-like characteristics, are tumorigenic and able to undergo asymmetric cell division to produce the heterogeneous cell types required to form a tumor) give rise to ovarian cancer is an idea currently receiving much attention. New research is beginning to unveil information regarding the identity and behavior of putative ovarian cancer stem cells. While progress has been made in selecting and characterizing these cells in vitro and in vivo based on cell surface marker expression, and their ability to recapitulate the tumor when passaged in mice, the origin of this cell population(s) is presently unclear. For example, while increasing evidence is pointing to secretory epithelial cells within the fallopian tube fimbriae epithelium as the source of serous ovarian cancer, there are no data available to support that these particular cells represent a normal tissue stem cell, or that these cells can be reprogrammed to adopt a stem cell-like phenotype.
Cancer stem cells are thought to retain phenotypes associated with a normal stem cell population, including a slow rate of growth. Cancer stem cells also express high levels of drug transporter molecules, including those characterized in ovarian cancer, thought to confer resistance to standard chemotherapeutics owing to their ability to efflux these drugs from the cell. If true, the idea that cancer stem cells are responsible for epithelial ovarian cancer has strong implications for disease recurrence. If such a cell population – presumed to be a very small proportion of the overall tumor cell population – is able to survive primary chemotherapy, then it is possible that these cells enter into a state of slow proliferation or dormancy during apparent disease remission. This period of remission can last for months to years, during which the location and niche of this cell population is not known. However, it is clear that something triggers these residual cancer cells to emerge again as recurrent, and often, chemoresistant disease.
Normal stem cells maintain epigenetic plasticity to allow for formation of differentiated progeny; it is conceivable that cancer stem cells also retain epigenetic plasticity, which may make them more vulnerable to epigenetic modulatory drugs (Figure 2). While combined epigenetic therapies with standard chemotherapeutic agents offers the opportunity to reactivate genes required to provoke a response to these drugs, single agent use of epigenetic therapeutics have largely been ineffective. It may be that epigenetic therapies will have utility when administered following completion of treatment using standard chemotherapeutics, as part of maintenance or consolidation therapy during the time when residual cancer cells are entering a state of slow growth or dormancy. In support of the feasibility of this approach, several HDAC inhibitors, including suberic bishydroxamic acid, trichostatin A and sodium butyrate, are effective at causing cell death of both actively proliferating and nonproliferating cells. My laboratory is currently conducting preclinical testing of several drugs that we have shown are more effective than cisplatin or paclitaxel at targeting slow-proliferating ovarian cancer cell populations in vitro. Similarly, Wei et al. have shown that Müllerian inhibiting substance is more effective at targeting ovarian cancer stem cells than standard chemotherapeutic agents.
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