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).
Personalizing Cancer Care with Circulating Tumor Cell Testing
The one word that cancer patients dread most is “metastasis.” Metastasis is the spread of cancer cells from the primary tumor into distant organs or tissues. In most cases of cancer-related death, it is not the primary tumor but rather the emergence of distant metastasis that claims the lives of cancer victims (Liberko 2013).
In order for cancer to metastasize, cells of the primary tumor must break away and infiltrate the circulatory system to be transported to another part of the body. These cancer cells flowing through the bloodstream are called circulating tumor cells (CTCs) (Wang 2011). In recent years, technological advances have given clinicians the ability to collect and evaluate CTCs from a cancer patient’s blood sample. These innovations have paved the way for new diagnostic and therapeutic strategies based upon quantitative and qualitative analyses of CTCs (Liberko 2013).
Counting the number of CTCs in a blood sample, which is described as quantitative CTC analysis, has emerged as a powerful prognostic tool: more CTCs correlate with a poorer outcome, and the prognostic information provided by CTCs can supplement the information obtained by imaging studies (Cristofanilli 2004; Cohen 2008; Negin 2010; Bidard 2011). CTCs can originate either from the primary tumor or metastatic tumors, and they are extremely rare, with one CTC being estimated to exist for one billion normal blood cells even in a person with advanced cancer (Yu, Stott 2011). Quantitative CTC testing provides prognostic value in several ways. For example, it can help predict tumor recurrences after surgical treatment (Peach 2010; Galizia 2013; Liberko 2013; Negin 2010; Cristofanilli 2007; Wulfing 2006). Moreover, CTCs can be used as a “surrogate marker” to indicate the potential spread of the tumor even in the absence of visible metastases (Gazzaniga 2013). It is important to remember that the number of CTCs is not simply an indication of tumor size, but it reflects other characteristics, such as vascularity and invasiveness (Yu, Stott 2011).
While quantitative CTC testing has been a boon in the battle against cancer, another aspect of CTC testing – qualitative CTC analysis – is emerging as a powerful tool. Cutting edge technology has allowed methods for evaluating CTCs to evolve from simply counting their number to characterizing their intricate molecular properties (Dong 2012; Rahbari 2012; Boshuizen 2012).
A major hurdle in the treatment of metastatic cancer is that tumor cells that break away from the primary site often evolve and develop different metabolic properties than the original tumor from which they emerged. This presents several problems because physicians often rely upon molecular analysis of a tissue sample from a primary tumor to guide treatment. For example, once a patient is diagnosed with cancer and a tumor is identified, a tissue sample (biopsy) is often taken from the tumor and sent to a pathologist for molecular analysis. This elucidates the metabolic properties of the tumor cells and allows oncologists to select interventions with a higher likelihood of success based upon the molecular characteristics of the cancer cells. However, in several cancer types, molecular differences have been observed between primary and metastatic tumors even within the same patient (Cavalli 2003; Smiraglia 2003). Interventions developed based upon molecular analysis of the primary tumor may, therefore, not be effective against metastatic tumors due to these differences (Biofocus 2011).
Qualitative CTC analysis represents a major step toward overcoming this barrier. Characterization of the molecular and genetic properties of CTCs allows oncologists to select a drug regimen that may be more effective against metastatic tumors. Using a process known as “chemosensitivity testing,” pathologists can analyze the properties of CTCs and determine which chemotherapeutic drugs are likely to kill the cells based upon their specific genetic makeup. Oncologists can then develop a treatment regimen consisting of drugs to which the patient’s CTCs are susceptible (Biofocus 2011; Rüdiger 2013).
Although qualitative CTC analysis stands at the cutting edge of cancer care currently available, such services are accessible for most cancer patients through organizations such as the International Strategic Cancer Alliance (http://is-canceralliance.com/) and Biofocus® (http://www.biofocus.de/de/onkologie/ueberblick/ueberblick/). Services such as these allow cancer patients to submit a blood sample to highly specialized labs to undergo qualitative CTC analysis, the results of which are reported back to the patient who can then share them with his or her oncologist (Biofocus 2011).
While the sensitivity and accuracy of these qualitative CTC analyses varies with cancer type, cancers of epithelial cell origin, such as endometrial cancer, are usually good candidates for these procedures (Biofocus 2011). Individuals interested in pursuing CTC testing can contact the International Strategic Cancer Alliance using the contact info below for more information.
International Strategic Cancer Alliance
873 E. Baltimore Pike #333