Novel and Emerging Strategies
The Power and Promise of Personalized Medicine
Although conventional treatment strategies for stage I endometrial cancer are quite successful, major advances in the areas of endometrial oncology and chemotherapy research have allowed for the development of several promising therapies for recurrent and late stage endometrial cancer patients (Schiavone 2012; Zagouri 2010).
By capitalizing on advances in DNA sequencing and genomics, researchers and clinicians are now able to individualize endometrial cancer treatments in accordance with the unique biology of each patient’s cancer (Westin 2012). For example, if genetic profiling of a patient’s tumor sample indicates a reliance on a specific growth signaling pathway that healthy endometrial cells do not rely heavily upon, then proteins important to this pathway would represent promising drug targets (Moreno-Bueno 2003; Westin 2012; Katoh 2013).
In addition, there are a variety of other pathways being identified as important in the development of endometrial cancer, such as the phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways (Slomovitz 2012). These pathways can be modulated by pharmaceutical agents, and research is underway to identify agent(s) that favorably alter the course of this disease (Janku 2012; Kang 2012; Suh 2013).
Personalized Medicine and Trastuzumab. One promising drug target in endometrial cancer is the Human Epidermal Growth Factor Receptor 2 (HER2) protein (Grushko 2008). This receptor, which transverses the outside surface of cells (ie, plasma membrane), is critical for growth signaling. In the case of certain subsets of endometrial cancer, the HER2 gene gets copied excessively, and the ensuing overabundance of HER2 protein has independent prognostic significance (Hetzel 1992; Morrison 2006; Grushko 2008; Slomovitz 2004).
By sequencing the DNA of endometrial cancer patients and using additional cellular and molecular biology tools, researchers and clinicians are now able to determine which endometrial cancer patients would benefit from treatment with trastuzumab (Herceptin®), a synthetic antibody that targets HER2 (Santin 2008).
Temsirolimus and the Inhibition of Endometrial Cancer Cell Metabolism
mTOR is a key protein involved in cellular growth, aging, survival, and metabolism (Hay 2004; Hung 2012; Johnson 2013). Cancer cells have developed a variety of means to modulate mTOR activity to help drive their high growth and metabolic rate. Given the links between cellular growth and metabolism on one hand, and cancer development on the other, inhibitors of mTOR have been hypothesized to have potent anti-cancer properties, and specific compounds showed positive responses in clinical trials (Faivre 2006). With respect to endometrial cancer, the mTOR inhibitor temsirolimus (Torisel®) was shown to have significant anti-cancer properties; response rates as high as 83% were reported in a phase II clinical trial involving women with recurrent or metastatic endometrial cancer (Oza 2011; Suh 2013).
Given the significant metabolic changes that occur during endometrial cancer development and the greater prevalence of endometrial cancer among patients with metabolic and endocrine diseases, including diabetes, anti-diabetic drugs have received interest for endometrial cancer prevention (Berstein 2004; Brinton 2007; Friberg 2007; Lai 2013; Zhang, Su 2013). One such anti-diabetic agent is metformin, a drug that lowers blood glucose levels by reducing the ability of the liver to produce new glucose and also increases the ability of muscle cells to uptake glucose from the blood (Mu 2012; Galuska 1994).
A variety of epidemiological studies have shown that diabetic patients taking metformin are significantly less likely to develop a variety of cancers, including pancreatic, liver, colorectal, and breast cancer (Evans 2005; Jiralerspong, Gonzalez-Angulo 2009; Jiralerspong, Palla 2009; Zhang, Gao 2013; Zhang, Li 2013). A variety of preclinical studies have shown that metformin inhibits the proliferation and promotes the death of endometrial cancer cells (Cantrell 2010; Xie 2011; Zhang 2011).
Prominent mechanisms by which metformin combats endometrial cancer appear to be through promotion of progesterone receptor expression and the reversal of progestin resistance in endometrial cancer cells (Zhang 2011; Xie 2011). Since endometrial cancer is largely an estrogen-driven disease, one of the treatments is to administer progesterone or synthetic progestins, which counter the action of estrogen in the endometrium. However, a major hurdle for this treatment approach is that the target for progesterone and synthetic progestins, the progesterone receptor, is often downregulated in endometrial cancer cells, especially following long-term treatment with a synthetic progestin. This negates the effects of progesterone or synthetic progestins, even if ample concentrations are available. In an experimental study, scientists administered metformin along with the synthetic progestin medroxyprogesterone acetate (MPA). They found that metformin markedly increased the expression of the progesterone receptor and had synergistic activity with MPA to decrease proliferation of the cancerous cells (Xie 2011). Likewise, researchers in China conducted an experimental study and concluded similarly that metformin “reversed progestin resistance, enhanced progestin-induced cell proliferation inhibition, and induced apoptosis in progestin-resistant [endometrial cancer] cells” (Zhang 2011).
Bevacizumab and the Inhibition of New Blood Vessel Formation in Endometrial Tumors
As tumors grow, they constantly form new blood vessels to provide cancerous cells with a blood supply that can deliver nutrients, energy sources, and oxygen, and remove waste products (Lodish 2000). This process of generating new blood vessels, called angiogenesis, appears to be promoted by several pathways, the most intensively studied one being dependent on a protein called vascular endothelial growth factor (VEGF) (Lodish 2000; Li 2010). Bevacizumab (Avastin®), a synthetic antibody that binds to VEGF, was developed to block angiogenesis and hence decrease tumor growth (Ferrara 2004). Preclinical studies showed promising results for bevacizumab in inhibiting endometrial cancer growth and clinical trial results documented the efficacy of this new anti-cancer treatment modality. Additional clinical trials are ongoing and further studies are needed to explore this therapeutic agent (Aghajanian 2011; Suh 2013; Morotti 2012).