In the ROR project, follow-up studies of the pharmaceutical properties of KAN0439834 show that they probably are better than previously assumed with respect to uptake and penetration of the substance to the cancer. The new studies indicate that dosing 2-3 times a day at 65-300 mg gives a concentration in the body that may be sufficient to exert an effect on solid tumors. However, the effect of KAN0439834 on solid tumors cannot be demonstrated in mice since the substance is metabolized too quickly in that species. Therefore, KAN0439834 and related substances will be tested against human solid tumors in an established zebra fish model for tumor growth and metastasis. This will allow effect studies of the ROR inhibitors at concentrations that are expected to be achievable in humans.
Further, the effects of KAN0439834 and three new drugs have been evaluated in tumor cells isolated from blood, lymph and bone marrow from nine patients. The background to this study is that new drugs such as Ibrutinib and Idelalisib give effect in 70-80% of patients with chronic lymphocytic leukemia (CLL). However, a so-called complete remission (the disappearance of symptoms) has only been reached in limited number of these patients. The lack of effect is particularly evident in the bone marrow. Since complete remission in cancer is generally linked to a longer survival, there is a need for drugs that work in a new way. Kancera has previously shown that the candidate drug KAN0439834 effectively kills patient CLL cells from blood and lymph in the laboratory and also in animal studies of the human disease. The present study, conducted by Prof. Håkan Mellstedt’s team at the Karolinska Institute, shows that Kancera’s ROR inhibitors are also effective in killing CLL cells from bone marrow which is a capacity wanted as a complement to the currently registered drugs against CLL.
In the Fractalkine project, Kancera has now established the network of leading cancer and pain scientists that in a collaborative project will evaluate the drug candidate KAN0440567 (AZD8797) in an advanced animal model closely resembling the human form of pancreatic cancer. Further, Kancera has synthesized and quality controlled the salt form of the drug candidate that will be used in the collaborative project and conducted a dosing study in mice. The results from this study support that an effective dose of the drug candidate can be achieved in mice via oral administration.
About the ROR project
ROR is a family of receptors, ROR1 and ROR2. The ROR receptors mediate signals for growth and survival. Originally ROR was linked to fetal development, but it is now known that they also contribute to cancer cell development and proliferation. Professor Håkan Mellstedt, Kancera´s co-founder and professor at the Karolinska Institute, and his colleagues have shown that Kancera´s ROR inhibitors have the ability to kill cells from tumors in pancreas, and leukemia cells. Professor Mellstedt and his colleagues as well as independent researchers have shown that ROR is also active as a target in prostate, breast, skin and lung cancer.
Because ROR primarily generates a survival and growth signal to tumor cells but is inactive in healthy cells in adults, there are good prospects that a drug directed against ROR hit the tumor much harder than the surrounding healthy cells. Kancera and Professor Mellstedt have shown that inhibition of ROR leads to that cancer cells eliminate themselves by cellular suicide. Against this background, there are reasons to anticipate that a ROR-targeted drug is both safer and more effective than several chemotherapies currently used to treat cancer.
About the Fractalkine project
Fractalkine is an immune regulatory factor that sends signals via the CX3CR1 receptor, also called G-protein coupled receptor 13 (GPCR13). In the healthy individual, Fractalkine and its receptor regulate migration of immune cells from the blood capillary wall into areas where the immune system is needed. Animal studies show that Fractalkine and its receptor are not essential for survival and that important immune functions remain intact indicating that inhibition of the Fractalkine signaling by a drug probably will be tolerated without significant adverse effects. Fractalkine and its receptor have been linked to the growth and proliferation of pancreatic, breast and prostate cancer. Also, cancer cells that have the Fractalkine receptor on their surface migrate towards nerve ends that have Fractalkine on their surface. Thus, cancer cells are led to surround and apply pressure on nerves and thereby cancer pain may arise. Another proposed mechanism for how Fractalkine and its receptor affect the development of tumors is that they contribute to the transformation of the body's macrophages from being a threat against the cancer (the M1 form) to supporting the cancer (the M2 form). This mechanism is also suggested as a predictive factor for responsiveness to the new immuno-oncology drugs that act through PD-1 and PD-L1 such as nivolumab, pembrolizumab and pidilizumab. During 2014 and 2015 studies have been published demonstrating that the absence of Fractalkine in tumor cells is a significant marker for how successful the immuno-oncology treatment is expected to be (see e.g. the publication in Nature on November 27, 2014, Vol. 515, pp 563). In the light of these observations, there are good reasons to further study if inhibition of the Fractalkine signaling with KAN0440567 (AZD8797) has the potential to increase the proportion of patients responding to the new immuno-oncology drugs that act through PD-1 and PD-L1.
About Kancera AB
Kancera develops the basis for new therapeutics, starting with new treatment concepts and ending with the sale of a drug candidate to international pharmaceutical companies. Kancera is currently developing drugs for the treatment of leukemia and solid tumors, based on blocking survival signals in the cancer cell and on addressing cancer metabolism. Kancera’s operations are based in the Karolinska Institutet Science Park in Stockholm and the company employs around 12 people. Kancera shares are traded on nasdaq first north and the number of shareholders was around 7400 as of July 31, 2015. Remium Nordic AB is Kancera’s Certified Adviser. Professor Carl-Henrik Heldin and Professor Håkan Mellstedt are board members and Kancera´s scientific advisers.
For further information, please contact,
Thomas Olin, CEO: +46 (0) 735 20 40 01
Kancera AB (publ)
Karolinska Institutet Science Park Banvaktsvägen 22
SE 171 48 Solna
Please visit the company website; https://www.kancera.com