Veteran cancer researcher Prof Emeritus Alexander Levitzki of Hebrew University of Jerusalem says new findings show a link between colorectal cancer and melanoma drug treatment known as "NT157".

Cancer is a highly complex disease in which the tumour recruits its surrounding tissue, as well as the immune system to support and promote its own growth.

This realisation explains why tumour therapy has been difficult for physicians.

Researchers now realise that not only does the tumour need to be targeted, but also its microenvironment and the immune system, which is subverted by the tumour to support it.

Two studies in the October 2015 print journal, Oncogene, focus on new potential drug-treatment research through a careful study of, and link between, colorectal cancer and melanoma.

Long-time cancer researcher Alexander Levitzki, Wolfson Family Professor Emeritus of Biochemistry at the Hebrew University of Jerusalem, and his senior colleagues, Efrat Flashner-Abramson and Dr Hadas Reuveni, and other colleagues, describe a double-edged molecule known as NT157 and its action against metastatic human melanoma.

In an accompanying article in the same journal, Prof Michael Karin, a highly acclaimed scientist from the University of California, San Diego, in collaboration with Prof Levitzki's laboratory, shows the dramatic therapeutic effects of NT157 on colon cancer in a mouse model, which faithfully mimics the human disease.

This unique family of compounds inhibits the action of proteins within the tumour itself, the action of these two cancer-driving proteins in the cancer-supportive microenvironment, as well as the action of "pro-tumour" immune cells, according to Prof Levitzki.

These molecules target two different proteins, comprised of a completely different mechanism of action.

A family of small organic molecules, which fulfils these aims, was developed by the Hebrew University's Alexander Silberman Institute of Life Sciences, in collaboration with the oncological pharmaceutical company, TyrNovo, which licensed NT157 from the Yissum Research Development Company of the Hebrew University of Jerusalem.

In his five decades of cancer research, Prof Levitzki has been the recipient of many international awards, including the Wolf Prize for Medicine.

As part of the NT157 research, the mechanism of these molecules was deciphered by  Flashner-Abramson as part of her PhD thesis in the Levitzki laboratory, and by Dr Reuveni, CEO of TyrNovo (and previously NovoTyr Therapeutics Ltd.).

These molecules target two different proteins, comprising of a completely different mechanism of action.

This action was highly unexpected and unforeseen.

Dr Elza Sanchez-Lopez, from UC San Diego Prof. Karin's lab, conclusively shows that due to the dual targeting feature of NT157, both the tumour and conducive microenvironment became suppressed; a highly effective activity 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 the paper, formally titled 'Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling.'

Signal transducer and activator of transcription 3 (Stat 3) is a protein that has attracted much interest as a target for anti-cancer drugs.

Stat 3 is a member of a family of seven latent cytoplasmic proteins (organisms such as bacteria, which lack a cell nucleus) and that function as key mediators of cytokine (small proteins) and growth factor signalling.

In the second paper, titled 'Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling,' researchers looked at the tumour microenvironment (TME).

TME exerts critical pro-tumourigenic effects through cytokines and growth factors that support cancer cell proliferation, survival, motility (capability of movement), and invasion.

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.

Tumour 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 harbour oncogenic mutations.

As in the case of melanoma, anti-cancer drugs for CRC are frequently ineffective against cancer-cells that are therapeutic target which concomitantly affect the malignant behaviour 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-tumour activity.

A prospective study of a cohort of 210 CRS patients shows that tumour size and depth of invasion significantly correlate with IGF-1 and IGF-1R, an insulin-like growth deficiency. 

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, tumours 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 paper’s authors.

Reference

Flashner-Abramson, Klein, Mullin et al. 'Targeting Melanoma with NT157 by Blocking Stat3 and IGF1R Signaling', Oncogene, October 2015

Rampias, Faviccio, Giamas et al. 'Targeting Tumor Stroma Crosstalk: the example of the NT157 inhibitor', Oncogene, October 2015

Source: Hebrew University of Jerusalem