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Small Organic Compound (NT157) Inhibits IGF1R-IRS1/2 & STAT3 Signaling Pathways; May Be Effective As “Double-Agent” Against Both Melanoma & Colon Cancer; NT157 Is Licensed by Israel’s TyrNovo Onco-Pharma Company

Cancer is a highly complex disease in which the tumor recruits its surrounding tissue, as well as the immune system, to support and promote its own growth. This explains why tumor therapy has been difficult for physicians. Researchers now realize that, not only does the tumor need to be targeted, but also its microenvironment and the immune system, which are both subverted by the tumor to support its growth. Two studies published recently in Oncogene focus on new potential-drug-treatment research through a careful study of, and link between, colorectal cancer (CRC) and melanoma. In one article, published online on September 14, 2015, long-time cancer researcher Alexander Levitzki (photo), Ph.D., Wolfson Family Professor Emeritus of Biochemistry at the Hebrew University of Jerusalem, and his senior colleagues, Efrat Flashner-Abramson, Ph.D., and Hadas Reuveni, Ph.D., together with additional colleagues, described a small organic molecule known as NT157 and its action against metastatic human melanoma. Professor Levitzki and his team showed that NT157 acts as a dual-targeting agent that blocks two different signal transduction pathways that are central to the development and maintenance of multiple human cancers. They showed that NT157 targets, not only the IGF1R-IRS1/2 signaling pathway, as previously reported, but also the Stat3 signaling pathway, and that the compound demonstrates remarkable anti-cancer characteristics in A375 human melanoma cells and in a metastatic melanoma model in mice. In the other Oncogene article, published online on June 29, 2015 article, Professor Michael Karin, Ph.D., a highly acclaimed scientist from the University of California, San Diego (UCSD), in collaboration with Professor Levitzki's laboratory, reported the dramatic therapeutic effects of NT157 on colon cancer in a mouse model that faithfully mimics the human disease. In this UCSD-led study, the researchers looked very closely at the tumor microenvironment (TME). The authors noted that the TME exerts critical pro-tumorigenic effects through cytokines and growth factors that support cancer cell proliferation, survival, motility and invasion. Insulin-like growth factor-1 (IGF-1) and signal transducer and activator of transcription 3 (STAT3) stimulate colorectal cancer development and progression via cell autonomous and microenvironmental effects.

Using the unique inhibitor NT157, which targets both IGF-1 receptor (IGF-1R) and STAT3 signaling pathways, the UCSD scientists and colleagues showed that these pathways regulate many TME functions associated with sporadic colonic tumorigenesis in CPC-APC mice, in which cancer development is driven by loss of the Apc tumor suppressor gene.

They showed that NT157 causes a substantial reduction in tumor burden by affecting cancer cells, cancer-associated fibroblasts (CAFs), and myeloid cells. They reported that decreased cancer cell proliferation and increased apoptosis were accompanied by inhibition of CAF activation and decreased inflammation.

In addition, they said that NT157 inhibited expression of pro-tumorigenic cytokines, chemokines, and growth factors, including IL-6, IL-11, and IL-23, as well as CCL2, CCL5, CXCL7, CXCL5, ICAM1, and TGFβ; decreased cancer cell migratory activity, and reduced cancer cell proliferation in the liver.

In conclusion, they wrote that “NT157 represents a new class of anti-cancer drugs that affect both the malignant cell and its supportive microenvironment.”

NT157 inhibits the action of proteins within the tumor itself; inhibits the action of two cancer-driving pathways in the cancer-supportive microenvironment; and also inhibits the action of "pro-tumor" immune cells, according to Professor Levitzki. The NT157 molecules target two different proteins that have completely different mechanisms of action.

The family of molecules including NT157 was developed by the Hebrew University's Alexander Silberman Institute of Life Sciences, in collaboration with the oncological pharmaceutical company, TyrNovo (headquarted in Herzliya, Israel), which licensed NT157 from the Yissum Research Development Company of the Hebrew University of Jerusalem.

As part of the NT157 research, the mechanism of action for these molecules was deciphered by Dr. Flashner-Abramson, as part of her Ph.D. thesis in the Levitzki laboratory, and by Dr. Reuveni, CEO of TyrNovo (and previously NovoTyr Therapeutics Ltd.). These molecules target two different proteins, having completely different mechanisms of action.

Such dual targeting by a single compound was highly unexpected and unforeseen.

Dr. Elza Sanchez-Lopez, from Professor Karin's lab at UCSD, conclusively shows that, due to the dual-targeting feature of NT157, both the tumor and the conducive microenvironment become suppressed; highly effective activities against colon cancer.

"The understanding that cancer is a manifestation of signal transduction gone awry has led to the development of 'targeted therapy' or 'signal transduction therapy,' aimed at cancer-driving proteins," according to authors of the UCSD-led study.

STAT3 is a protein that has attracted much interest as a target for anti-cancer drugs. The STAT3 protein is a member of a family of seven latent cytoplasmic proteins that function as key mediators of cytokine and growth factor signaling.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer, with more than 1.2 million cases each year in the United States. While improved early detection and patient stratification (categorization), results in a significant reduction of mortality, most improvement has been limited to early stage CRC. In patients with advanced stages of the disease, morbidity and mortality remain high.

Tumor development is highly dependent on intricate interactions between multiple cell-types, in addition to malignant epithelial (membranous tissue covering internal organs and other internal surfaces of the body) cells that harbor oncogenic mutations.

As in the case of melanoma, anti-cancer drugs for CRC are frequently ineffective against cancer-cells that are therapeutic targets which concomitantly affect the malignant behavior of cancer cells and the supportive function of the TME is of particular importance.

Therapies that target TME components in addition to cancer cells, should have strong anti-tumor activity.

A prospective study of a cohort of 210 CRC patients has shown that tumor size and depth of invasion significantly correlate with levels of IGF-1 and IGF-1R.

Specific signal transduction inhibitors, a category of anti-cancer drugs that inhibit the enzymes essential to the growth and survival of cancer cells while causing little or no damage to non-cancer cells, are rarely effective in treating the disease.

In most cases, tumors possess primary drug resistance due to their inherent heterogeneity - one of the underlying reasons that make treatment of cancer difficult. Resistance to drugs is due to genomic instability and acquisition.

"Our results strongly support further clinical evaluation of NT157 and similar compounds in sporadic human CRC," according to the UCSD-led paper's authors.

[Press release] [Oncogene abstract September 14] [Oncogene abstract June 29] [American Friends of Hebrew University article]