The Science of Cancer

Updated: April 30, 2006

Cancer is a genetic disease resulting in deregulated cell growth. Tumor suppressor genes and oncogenes inhibit or stimulate cell growth or proliferation and are normally in balance. Mutations in either or both of these gene classes can lead to cancer. Over the past 20 years, much research has focused on inhibiting the growth of tumor cells by altering the activity of either oncogenes or tumor suppressors, so that normal growth properties are restored. This approach has met with limited success for several reasons:

  1. Tumor cells can acquire mutations rapidly, and drugs designed to kill the tumor cell or alter protein activity are often countered with further mutations, thereby leading to drug resistance;
  2. Many of the oncogenes and tumor suppressors have normal counterparts that are required for normal cell functions, so that inhibiting their activity often causes serious side effects and toxicities;
  3. The mechanisms of action of some oncogenes and tumor suppressors are poorly understood limiting the development of more specific drug therapies.

For these reasons, alternate approaches to the management and cure for cancer have been actively pursued.

The Anti-Angiogenic Approach

One anticancer approach that has received much attention in recent years is the targeting of the blood supply of the tumor. If tumors are prevented from recruiting new blood vessels for nutrients (through a process called angiogenesis) they cannot grow beyond a very small size and cannot spread (metastasize) to other parts of the body, rendering them essentially harmless to the patient. This approach is attractive because, unlike tumor cells, the cells that form blood vessels do not acquire mutations at any appreciable rate and, therefore, acquired drug resistance is unlikely. In addition, the Company believes that the growth of blood vessels around tumors is a different process than normal angiogenesis in adults suggesting it is possible to develop non-toxic drug regimens for treating cancer. Normal angiogenesis occurs in adults primarily in wound healing and certain reproductive functions. Finally, the molecular steps that result in angiogenesis are becoming better understood, thereby providing new targets for anti-angiogenic drug design.

Lysolipids such as sphingosine-1-phosphate (S1P) have been demonstrated to play a key role in tumor angiogenesis and cancer-cell growth. The Company is pursuing strategies to inactivate S1P to inhibit the growth and metastasis of tumors. The importance of S1P in angiogenic- dependent tumors makes S1P an excellent target for cancer treatment. Based on findings in the published scientific literature, as well as our own data using Sphingomab™, the Company believes that antibody neutralization of extracellular S1P could result in a marked decrease in cancer progression in humans as a result of inhibition of blood-vessel formation with concomitant loss of the nutrients and oxygen needed to support tumor growth. Furthermore, recent research suggests that many angiogenesis inhibitors may also act as anti-invasive and anti-metastatic compounds, which could also aid in the mitigation of the spread of cancer to sites distant from the initial tumor. Thus, neutralizing tumorigenic lipid growth factors such as S1P has several potential mechanisms of action, including: (i) direct effects on tumor cell growth, (ii) the indirect anti-angiogenic effect on vascular endothelia cells and (iii) the indirect anti-angiogenic effect of preventing the release and action of other pro-angiogenic growth factors. The Company believes that Sphingomab™ may also be just such an anti-metastatic therapeutic in addition to an anti-angiogenic therapeutic (see below).

A Novel Approach to a Proven Mechanism of Cancer Treatment

The identification of signaling components that promote tumor growth is a critical step in discovering therapeutic interventions that will reduce the suffering, morbidity, and mortality of cancer. Sphingosine-1-phosphate (S1P), a key component of the sphingolipid signaling cascade, is a pleiotropic tumorigenic growth factor. S1P promotes tumor growth by stimulating cell proliferation, metastasis, and cell survival. Recent studies indicate that S1P also promotes tumor angiogenesis by supporting the migration and survival of endothelial cells when they form new vessels within tumors. Importantly, sphingosine kinase (SPHK), the enzyme responsible for S1P production, is an oncogenic protein, further suggesting that S1P is a potentially therapeutic target for addressing cancer.

Sphingomab™ is a specific, anti-S1P mAb directed against S1P

This antibody acts as a therapeutic molecular sponge to selectively absorb S1P, thus lowering the effective extracellular concentrations of this tumor-facilitating factor. As a consequence of extensive preclinical animal studies, it is anticipated that this antibody would result in the reduction of tumor volume and metastatic potential in cancer patients as well as the simultaneous blockage of new blood-vessel formation that would, otherwise, feed the growing tumor. In addition, the Company believes that the ability of S1P to protect cells from apoptosis could be reversed by the antibody, thus increasing the efficacy of standard pro-apoptotic chemotherapeutic agents (see Figure 3 below)

Figure 3.

Cartoons illustrating the action of Sphingomab™, the anti-S1P antibody