Technology Opportunities

Ido Wolf, Tamar Rubinek, Bella Kaufman, Lilach Abramovitch, H. Phillip Koeffler, Chaim Sheba Medical Center, Israel

Abstract

Pancreatic cancer is a fatal disease and the 5 years survival of patients who suffer from advanced disease is less than 10%. Current treatment for metastatic pancreas cancer consists of chemotherapy and is unsatisfactory, with a median survival following chemotherapy of about 6 months. Breast cancer, in which malignant cells develop in the tissues of the breast, is the most common cancer among women, and the second most common cause of cancer death in women in the United States.

Klotho, a transmembrane protein, is expressed in the brain, kidneys and pancreas. It is also expressed in various sex-hormone responsive organs including placenta, testis, prostate and ovary. Klotho can be shed and act as a hormone, and has been identified previously as an inhibitor of the insulin growth factor (IGF)-1 pathway in hepatocytes and muscle cells.

Our data suggest high levels of klotho protein expression in normal breast samples and normal pancreatic cells, but very low expression in cancerous breast cells or cancerous pancreatic cells. In addition, noted inhibition of breast cancer cell growth following over-expression of klotho protein, and growth enhancement of klotho protein-expressing cells following klotho protein knock-down; and revealed modulation of the IGF-1 and the insulin pathways by klotho protein. Taken together, the results suggest klotho protein as a novel breast cancer tumor suppressor. Moreovere, we have found additive effects of klotho and various chemotherapy agents and noted more than 80% inhibition of PANC-1 cells by the combination of klotho and low dose of chemotherapy. Animal studies demonstrate a therapeutic effect of Klotho. Treatment of mice with Klotho protein resulted in a significant dose response inhibition of tumor growth. The present invention relates to the use of the klotho protein for the treatment and diagnosis of cancer, such as breast cancer and pancreatic cancer as well as other IGF-1 dependent cancers.

Recently, we have characterized the specific and selective domain of the protein, with selective anti-tumor, including a unique mutation introduced in the active domain, which enhanced its activity and specificity.

The Need

Pancreatic cancer is responsible for 6% of cancer death each year. Pancreatic cancer has the highest fatality rates of all cancers, and is the 4^th highest cancer killer in the US among both men and women. Each year about 33,000 individuals in the US are diagnosed with this condition and more than 60,000 in Europe. The only therapy currently available for metastatic pancreatic cancer is standard chemotherapy which adds about 1 to 2 months to the median survival time.

Breast cancer is the leading cause of cancer-related mortality among women worldwide. In 2007, more than 470,000 cases of the disease were diagnosed in the seven major pharmaceutical markets. High unmet needs still persist for this tumor type. Despite recent drug approvals in the adjuvant and metastatic setting, the overall survival remains below five years.

The breast cancer (BC) market is a steadily growing market due to effective treatments which have decreased mortality and resulted in a longer duration of therapy. The five-year survival rates for women with BC have increased from under 70% 50 years ago to around 90% now. In 2007, we estimate that sales grew by 22% compared to 2006, generating revenue of over US$11.3 billion. Branded therapies were responsible for 92% of this total (US$10.5 billion). Breast cancer is the most common cancer among women.

Cancer can only be positively diagnosed by biopsy, which involves removal of a small tissue sample. A substantial need remains for a more accurate and less invasive means of determining the presence of cancer. Klotho blood tests can use for diagnosis.

Potential Applications

Klotho is a potentially potent and specific therapeutic agent for the treatment of cancer patient. Administration of Klotho in combination with standard chemotherapy may greatly approve cancer patient survival.

Monitoring blood levels of Klotho for early diagnosis of cancer and prognosis.

The major potential applications are breast and pancreatic cancer

Development Stage

· In vitro as well as in vivo studies have proved the concept of Klotho and its active domain as a potent diagnostic and therapeutic agent for cancer.

· Structure function analysis of Klotho protein resulted in the active extra cellular subunit with the anti cancer activity.

· Biochemical studies of Klotho and its domain, in terms of structure function analysis to dissect its cellular mechanism of action and its anti-tumor activity.

Advantages

Protein / peptide drugs pose unique advantages over traditional small molecule drugs as they are targeted and specific for cancer types.

Given the importance of detecting cancer early in its development, and the potential harm that may occur as a result of false positives or false negatives from mammography and other techniques for screening of various types of cancer, a substantial need remains for a more accurate and less invasive means of determining the presence of cancer. Moreover, currently used techniques cannot predict cancer development among patients with benign breast cancer.

Contact: Sylvie Luria Ph.D. CEO

Technology Transfer Company

Tel Hashomer Medical Research, Infrastructure and Services Ltd.

Tel: +972-3-5305998 Fax: +972-3-5305944 Cell: +972-052-6667277

sylvie.luria@sheba.health.gov.il http://rnd.sheba.co.il/e/