Medullary Thyroid Cancer: Oncologic Research

More than 50% of all patients show signs of distant metastases at the time of diagnosis1. Prognosis remains abysmal, as 90% of patients die within 6 months of diagnosis due to distant metastases or local invasion8. Patients younger than 60 year of age with involvement limited only to the thyroid have a better outlook than older individuals with signs of metastasis5. Ultimately, ATC accounts for more than 50% of all thyroid malignancy-related deaths1.

Crizotinib (PF-02341066) is a potent inhibitor of c-Met and ALK. Anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) is a molecular subtype of NSCLC with at least 27 ALK-fusion variants identified. c-Met is the prototypic member of RTKs, which is the only known high-affinity receptor for hepatocyte growth factor (HGF). Binding of HGF to the c-Met results in receptor multimerization and phosphorylation of multiple tyrosine residues at the intracellular region.

According to a paper published by the Center for Diseases and Control, Lung Cancer has the highest mortality rate in the US than any other cancer type. In 2011, about 156,953 people died from the disease as about 207,000 cases of ailing lung cancer patients were diagnosed that year. This number is set to see an increase over the years if adequate care in research is not given .Song described Lung cancer, as Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) with the former being responsible for about 85% of diagnosis cases and deaths reported each year. The most common types of NSCLC include adenocarcinomas, large cell carcinomas, and squamous cell carcinomas and as expected, most of these NSCLC types are related to smoking. However, adenocarcinomas have been found in patients who never smoked. Common but inadequate ways of NSCLC treatment include surgery, radiation therapy , and chemotherapy (Witschi , 2001) but the most effective form of NSCLC treatment has been known to be targeted therapies (Nguyen et al. , 2011) . This research invention has taken cancer treatment to another level because of the specificity of the drug inhibitors used to target carcinomas, or protein kinases that involve in pathways of the cancer. Adequate research has led to efficient modifications to use of targeted-therapies for specific fusion genes that code for oncogenes and kinesin genes i.e the Kinesin Family 5B gene and the RET (Rearranged during Transcription). Song also

Most thyroid tumors can be readily diagnosed using histopathologic criteria, which allow the pathologist to differentiate benign from malignant lesions and guarantee an accurate classification for the majority of the variants of carcinomas derived from follicular epithelial cells. However, in most cases, the pathologist is confronted with thyroid lesions in which the distinction between benign and malignant can be quite subtle. The decision favoring one or another has clinical consequences and implies different modalities of treatment. For this reason, the approach to these challenging tumors should include ancillary techniques, immunohistochemistry and molecular profiling, that can improve the standard morphologic assessment (3).

The most common endocrine system malignancy in the Unites States is thyroid cancer. The majority of diagnosed thyroid cancers are classified as differentiated thyroid cancer (DTC). More specifically, these cancers are either papillary thyroid cancer (PTC) or follicular thyroid cancers (FTC), with 80.2% being diagnosed as papillary and 11.4% as follicular (Avram, 2012). DTC is the fifth most common cancer among females and has ten year survival rates of 97% for PTC and 94% for FTC (Khan et al., 2015; Marcus, Whitworth, Surasis, Pai, & Subramaniam, 2014). The majority of patients diagnosed with DTC receive a near-total or total thyroidectomy. Some patients also have lymph nodes or surrounding tissue removed as well dependent on metastases (Avram, 2012).

Under normal conditions, cells balance division and apoptosis, and these processes are accomplished and preserved by several biochemical “checkpoints” during the cell cycle2. When these checkpoints are affected, uncontrolled cellular proliferation and cancer can result. Two general classes of cancer genes are oncogenes and tumor suppressor genes. Oncogenes facilitate tumor formation by directly accelerating cell division, whereas tumor suppressor genes, when affected, allow uncontrolled growth that was normally suppressed2. Tumor suppressor gene loss usually affects a cell’s phenotype when both copies of the gene are lost, so null alleles can be present in a heterozygous state in cells without affecting cell and tissue phenotype. The loss of these genes can occur through genetic mutation or the epigenetic silencing of genes via promoter

In vitro: AMG 337 could inhibit MET kinase activity effectively, AMG 337 also showed exquisite selectivity for MET when tested against a diverse panel of over 400 protein and lipid kinases. In addition, AMG 337 was found to inhibit HGF-dependent MET phosphorylation. Furthermore, the treatment with AMG 337 could only affect the viability of two gastric cancer cell lines (SNU-5

Less evasive is just the removal of the lobe that contains the tumor (lobectomy). If the cancer has spread to other parts of the body, such as the lymph nodes, these can also be removed. Sometimes radioactive treatment is recommended along with the removal of the thyroid gland. Radioactive iodine therapy (RAI) is always done for more advanced cancers, such as those that have been staged as T3 or T4 and follow-up hormone treatment is started. If RAI doesn’t appear to work and the cancer remains, external beam therapy, targeted therapy, and/or chemotherapy may be

approximately 80 - 90% of pancreatic cancers, 50% of colorectal cancers, 30% of thyroid cancers, 30% of NSCLC and 5% of breast and prostate cancers 13,14 [13,14]. RAS proteins are a family of GTPases activated by cell surface receptors by displacing guanosine diphosphate (GDP) molecules with guanosine triphosphate (GTP) molecules. Active GTP-RAS is then able to recruit and activate several intracellular signaling pathways, such as RAS-REF-MEK-ERK (also known as MAPK/ERK Pathway) and phosphoinositide-3 kinase (PI3K) pathway. In the RAS-RAF-MEK-ERK pathway, the RAS regulates the activity of downstream RAF proteins which are then able to phosphorylate and activate MEK. Activation of MEK, in turn, phosphorylates and activates ERK which is responsible for activating a range of transcription factors within the nucleus that are involved in cell proliferation 15 [15]. The other RAS dependent pathway is the complex PI3K pathway where the catalytic p110 subunit of the PI3K is activated that phosphorylates PIP2 to PIP3 or Phosphatidylinositol (3,4,5) Triphosphate which in turn phosphorylates and activates AKT, AKT plays a critical role in regulating cellular growth and apoptosis. Conversely, the tumor suppressor protein Phosphatidylinositol 3 Kinase Phosphatase with Tensin homolog (PTEN)

Cancer is one of the leading causes of death worldwide as it can develop in almost any organ or tissue. Significant advances in understanding the cellular basis of cancer and the underlying biological mechanisms of tumour has been vastly improved in the recent years (Jiang et al. 1994). Cancer is a genetic disease which requires a series of mutation during mitosis to develop, its characteristics can be associated with their ability to grow and divide abnormal cells uncontrollable while in the mean time invade and cause nearby blood vessels to serve its need. Even though many people are affected by cancer today, the abilities which cancer cells have make it hard to find a single effective treatment for cancer. The focus of research now lies

CXCL9 and CXCL10 (matrix degrading enzymes) also induce tumor cells to leave the tumor and eventually form additional metastases (the development of secondary malignant growths at a distance from a primary site of cancer) at distinct sites.

The incidence of thyroid cancer is rapidly rising in the US accounting for 62,980 cases with 1890 deaths every year[1]. It is the seventh most common cancer diagnosed in women and peaks earlier than in men. Despite its high prevalence, death rate from thyroid cancer is fairly stable from past many years. In general, thyroid cancer offers a good prognosis with an overall survival rate of approximately 90%[2]. Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) termed as differentiated thyroid cancer (DTC) contribute to majority of thyroid cancers sharing a superior prognosis. Medullary thyroid carcinoma (MTC), mostly acquired as a part of familial syndromes, display only modest cure rates. While surgical resection followed by radioiodine therapy remains the treatment of choice for localized thyroid cancer, it fails to eradicate tumors with aggressive behavior. In marked contrast to DTC, anaplastic carcinoma (ATC), an undifferentiated sub-type of thyroid cancer, has a higher propensity to locally invade nearby structures and metastasize rapidly. It approaches to almost 50% of all thyroid cancer-related deaths, the median survival being only six months[3]. The grim prognosis of ATC is due to the fact that it is diagnosed at an advanced stage which offers palliative treatment as the only option for patients suffering from the disease. Because of the chemo- and radio-resistant nature observed in aggressive thyroid cancers, many researchers have been

Multiple research reports bring solid evidence for the implication of Wnt/beta-catenin, PI3K/AKT/mTOR (phosphatidylinositol 3-kinases/protein kinase B/mammalian target of rapamycin), HGF/c-Met (hepatocyte growth factor/c-mesenchymal epithelial transition factor), and MAPK (mitogen-activated protein kinase) pathways, by alterations in one or more components of their structure.(5,16)Among these beta-catenin signaling and its targeted genes are known to actively participate in different biological processes during embryonic development and RCC.(17)

Validating the effects of candidate kinases using the Hek293 cells with inducible Htt full length (FL): We have obtained the Hek293 cell, which can express the FL Htt with 17Q and 43Q upon doxycycline treatment (Huang et al., 2015). We will carry out the kinase LOF and GOF experiments as described above in this cell lines to validate the results obtained in our initial assays using the HEK293 cells. We will closely monitor the total levels of Htt in these cells upon kinase LOF and GOF to determine the effect on kinase phosphorylation on Htt clearance. If we find effects in Htt clearance, we will examine the molecular mechanism.

In cancer cells, the normal control systems that prevent cell overgrowth and invasion such as tumour suppressor and cell cycle check point genes are disabled, therefore; they no longer require special signals to induce cell growth and division. As these cells grow, they develop new acquired characteristics, including changes in cell structure, decreased cell adhesion, amplification or inactivation of specific genes, expression of tumor markers, alternation in tissue architecture, change in extra cellular matrix and production of new enzymes (Kumar and Weaver, 2009). Cancer cells can spread to other parts of the body through the blood and lymph systems