The Technology

Fundamental research and proof-of-concept data accumulated over a period of more than 10 years provides compelling evidence that selective SK1 inhibitors have the potential to:

1. Display broad spectrum anti-cancer efficacy against both leukaemias and many solid tumours, such as prostate, lung, breast and colon cancers.

2. Exert a dual effect in solid tumour situations by simultaneously disabling a key mechanism underlying the capacity of tumour cells to display inappropriate survival, AND blocking the process of new blood vessel formation upon which the continued growth of tumours depends.

3. Find utility as single agents in their own right and be effective in combination treatments through their ability to sensitise tumour cells to other chemotherapeutic agents.

4. Be highly selective, due to the unique nature of the catalytic site of SK1 and the mechanism by which the enzyme is activated and acquires the ability to transmit oncogenic signals.

The research team at the IMVS was the first to identify the key role of SK1 in cancer and has achieved a dominant position in the area through its portfolio of patents. These patents potentially preclude others from developing SK1-based therapeutics in a range of disease states in the absence of appropriate commercial licenses from SDP.

SK1 catalyzes the formation of sphingosine-1-phosphate (S1P) from sphingosine as the final step in the conversion of the pro-apoptotic lipid ceramide to S1P, a molecule now known to suppress apoptosis (programmed cell death) and promote cell survival. The balance of the cellular concentrations of ceramide and S1P is a major contributor to determining whether a cell survives and proliferates or undergoes apoptosis. It has been shown that inhibition of SK1 reduces cellular levels of S1P and promotes apoptosis, effectively counteracting a major hallmark of all cancer cells – namely, their capacity for inappropriate cell survival.

Research data accumulated over a period of more than 10 years by the R&D team at IMVS, and others, presents compelling evidence to support the hypothesis that SK1 inhibitors of the requisite potency and selectivity have the potential to be effective anti-cancer agents, applicable to the treatment of a broad range of cancer types. This evidence can be summarised as follows:

Many cancers, including those comprising the most common forms of cancer (e.g. breast, lung, prostate and colon) show over-expression of SK1.
Induced over-expression of SK1 in normal cells causes them to acquire the transformed phenotype, including the ability to form tumours when injected into mice.
Induced expression of a dominant negative mutant of SK1, which specifically blocks the process by which endogenous SK1 is activated and acquires the ability to transmit oncogenic signals, reverses the transformed phenotype of cancer cells.
Small molecule inhibitors of SK1 block cancer cell proliferation in vitro and the growth of tumours in mouse models of cancer.
Other important human oncogenes, including Ras (one of the most commonly-mutated genes contributing to the development of many human cancers) work, at least partly, through the activation of SK1.
SK1 is involved in the direct activation, or transactivation, of other cell signalling pathways, including ones initiated from other cancer-associated molecules against which successful drugs have already been developed, e.g. the EGF receptor (targeted by Iressa), VEGF (targeted by Avastin), TNF (targeted by Etanercept) and oestrogen (targeted by Tamoxifen).
Inhibition of SK1 can overcome the resistance of cancer cells to other chemotherapeutic agents.
The product of SK1 activity (S1P) promotes angiogenesis (new blood vessel formation) through its action on specific cell surface receptors. Hence, in addition to blocking the anti-apoptotic/pro-survival effects of S1P, inhibition of SK1 would also be expected to inhibit angiogenesis, a process which is critical for the continued growth of solid tumours.

SDP Technology is prosecuting 11 patent families, including more than 70 patents and patent applications, in key world markets.

The patents cover many approaches to the treatment of cancer, including specific cancers such as breast cancer, and means of improving current cancer therapies where known agents have become ineffective (Tamoxifen resistance in breast cancer, for example). Importantly, they also provide an approach for inhibiting the elevated SK1 activity seen in cancer without eliminating baseline or normal activity. This may be important in reducing the potential for side effects from treatment.