Gastric Cancer, Or Stomach Cancer, Is The Second Leading Cause Of Cancer Deaths

I have learned the hard way that blogging is a dangerous business! About two weeks ago my poor, beleaguered laptop contracted a root virus from who-knows-where. Fortunately, I was able to take it offline before my identity was stolen and get it to some experts. Two weeks later, my hard drive has been wiped completely clean and Im basically starting over. It could have been worse.

INTRODUCTION

Nonetheless, in the interest of picking up where I left off lets go back to Foretinib. My last post focused on a phase II clinical trial of foretinib in renal cell carcinoma. Previously, I have also discussed early phase trials of foretinib in various solid tumors. More recently, preliminary research in cell lines has begun to elucidate whether foretinib may prove efficacious in treating gastric cancer.

GASTRIC CANCER

Gastric cancer, or stomach cancer, is the second leading cause of cancer deaths worldwide leading to approximately 750,000 deaths per year according to the World Health Organization. A large part of the reason for why gastric cancer is so deadly is that it is usually asymptomatic in the early stages. The earliest symptoms are very vague and can include indigestion, loss of appetite, and abdominal discomfort. These symptoms progress into generalized fatigue and bloating. By the time more severe symptoms such as abdominal pain, nausea, vomiting, diarrhea, weight loss, bleeding, anemia, and dysphagia occur the disease is fairly advanced and prognosis is very poor.

CAUSES

Infection by Helicobacter pylori is believed to be the cause of most stomach cancer. Only about 2% of patients with H. pylori infections develop gastric cancer, however, these comprise 65-80% of gastric cancer cases. Genetic factors have been identified in about 10% of cases. Additionally, tobacco smoking appears to be another major risk factor and doubles the relative risk for current smokers when compared to the non-smoking population. Furthermore, the American Cancer Society indicates that some foods, including smoked and/or salted fish and mean as well as pickled vegetables appear to increase the risk of stomach cancer. On the other hand, eating fresh fruits and vegetables that contain antioxidant vitamins appears to lower the risk.

TREATMENT

Currently, the most common treatment for gastric cancer is surgical resection. The surgeon removes a part of all of the stomach, as well as the surrounding lymph nodes, with the basic goal of removing all cancer and a margin normal tissue. The use to chemotherapy to treat stomach cancer has no firmly established standard of care because stomach cancer has not proven to be sensitive to most chemotherapeutic drugs. For these reasons, chemotherapy is most frequently used palliatively to reduce the size of the tumor, relieve symptoms of the disease, and increase survival time. Although, the relative benefits of using chemotherapeutic drugs, either alone or in combination, are unclear.

USE OF FORETINIB

The most severe forms of gastric cancer often over express c-Met. So, because previous trails have shown that foretinib is a tyrosine kinase inhibitor of c-Met investigators thought it might prove to be effective in treating gastric cancer. In a study published last year, in 2011, investigators used gastric cancer cell lines to evaluate the mechanism of action of foretinib and identify biomarkers indicative of a cellular response. The study found that foretinib inhibited the cell growth of gastric cancer cell lines by inhibiting not only c-Met kinase but also FGFR2 kinase. Their findings suggest that foretinib inhibits multiple receptor tyrosine kinases through signaling networks with c-Met or FGFR2 at their center. In one cell line (designated KATO-III), activation of EGFR, HER3, and c-Met all appeared to be FGFR2 dependent. Conversely, in a second cell line (designated MKN-45), activation of EGFR, HER3, FGFR3, and other receptor tyrosine kinases appeared to be c-Met dependent. Similar results in a second cell line (designated GTL16), which also demonstrates increase c-Met signaling, suggest that HER family receptors are biologically active in these c-Met amplified cell lines. These findings led investigators to knockdown HER3 expression, which led to decreased growth rate of the MKN-45 cell line.

Together, these results indicate that at least a portion of gastric cancers have an inter-connected receptor tyrosine kinase signaling network with a gene-amplified receptor tyrosine kinase at its core. This concept may explain why some drugs, such as gefitinib, may be ineffective because they target downstream receptor tyrosine kinases. However, the downstream molecules are dramatically inhibited once the upstream core receptor tyrosine kinase is targeted. For that reason, foretinib, which targets both c-Met and FGFR, both core receptor tyrosine kinases, may prove to be the most effective chemotherapeutic yet to treat gastric cancer.

SUMMARY

In summary, foretinib may prove to be the first of an effective, new class of drugs against gastric cancer cells. Further studies are required to assess the effect of foretinib on gastric cancer in patients with tumors characterized by c-Met or FGFR amplification mutations in clinical settings, which includes approximately 20% of cases.