Targeting the Salt Inducible Kinase 2 (SIK2) for cancer therapy

Approximately 200000 women worldwide are diagnosed with ovarian cancer of which around 7000 are in the UK. Early diagnosis is difficult and as a result 90% of those diagnosed have cancer which has spread beyond the ovaries. The standard care for patients involves surgery and chemotherapy and though the initial response to treatment is good, the majority of patients suffer from recurrence. Indeed the 5-year survival for women with advanced stage ovarian cancer is approximately 30%.
One of the main reasons for recurrence is that surgery is unable to remove 100% of the cancer cells and these can form the basis for the cancer to return and to spread to specific areas local to the original tumour. These local areas are rich in fat cells called adipocytes and there are factors in ovarian cancer cells which promote cancer growth in these adipocyte regions. We have identified one of these factors, a protein called Salt Inducible Kinase 2 or SIK2. We have evidence that reducing SIK2 levels in cell lines derived from human tumours reduces their proliferation and may stop them spreading in patients. We will try to identify a small molecule inhibitor of the SIK2 enzyme which can be used either alone or in conjunction with the current standard of care to help improve survival rates for women with ovarian cancer.

We previously showed that depletion of the Salt Inducible Kinase 2 (SIK2) in cancer cells leads to a significant decrease in cancer cell growth, delayed G1/S transition and decreased AKT S473 phosphorylation. Loss of SIK2 also sensitized cancer cells to the chemotherapeutic agent paclitaxel, in culture and in xenografts (Ahmed et al., Cancer Cell 2010). We have now been able to show that SIK2 plays a dual role in regulating two of the fundamental processes required for ovarian cancer cell metastasis to the adipocyte-rich intra-abdominal metastatic niche. Freshly isolated adipocytes obtained from human subjects induced SIK2 activation and inhibition of lipogenesis to facilitate fatty acid oxidation. SIK2 phosphorylated the regulatory subunit of PI3K, p85alpha at S154 and S541 and significantly activated the PI3K complex. We show that targeted depletion of SIK2 or its selective inhibition abolished adipocyte-induced activation of PI3K and prevented enhanced cancer cell proliferation. This key role of modulating the PI3K was validated in an established independent system of drug resistance. We found that SIK2 inhibition or targeted depletion, prevented Rapamycin-induced activation of PI3K and sensitized cancer cells to Rapamycin. We propose to develop a selective SIK2 inhibitor that could be used for preclinical and clinical evaluation for cancer treatment either as a single agent or in combination with standard of care treatment.

The primary aim of this work is to generate selective and potent inhibitors for SIK2 that could be utilized in patients with ovarian cancers to prevent tumour recurrence. If successful, such approach would have a significant health and financial impact. About 200,000 women are diagnosed with ovarian cancer each year with a median progression free survival of about 12 months. Significant prevention of recurrence would have a major impact on the survival and overall quality of life of ovarian cancer patients.
Because the cause of death of patients with ovarian cancer is almost always related to intestinal obstruction, vomiting and malnutrition, most patients are hospitalized for long periods for symptomatic relief. Hospital management includes extended stay, palliative operative procedures (e.g. gastostomy), total parentral nutrition, electrolyte imbalance correction and intensive care unit stay. Thus, the cost of end of life care for ovarian cancer patients is disproportionately high compared to other malignancies for which patients are managed in the community or by hospice care. Preventing ovarian recurrence or reducing its burden is likely to make ovarian cancer a chronic non-fatal condition that could be managed in the community. By doing so, significant economic savings would be achieved.

In addition to above implications for ovarian cancer survivors, the potential immediate benefit from a successful SIK2 inhibitor therapy is high. Attracting pharmaceutical investments in such therapy is possible given the role of SIK2 in ovarian cancer and its potential role in other cancers such as prostate cancer, lung cancer and lymphomas. The wider biological role of SIK2 in modulating a variety of pathways makes SIK2 an attractive target for therapy in a number of common conditions such as diabetes and inflammation. Thus, there are several potential therapeutic utilities for SIK2 inhibitors that makes our approach attractive for investments from industry.

In addition to the potential immediate impact on health (by treatment of cancer and other diseases), economic savings (by limiting end of life costs) and economic gains (by establishing investment opportunity from commercial partners), developing selective inhibitors for SIK2 is likely to have a major impact in promoting fundamental research into the biological role of this kinase. This could have long-term implications for generating as yet, unperceived, benefits. The role of SIK2 in regulating a wide variety of biological processes is summarized under "academic beneficiaries". A review of recent literature makes it clear that there is substantial interest in investigating the fundamental processes in which SIK2 is involved. The development of selective SIK2 inhibitors can only accelerate this research.