On April 22, 2016 Kancera reports that ROR inhibitors have been tested against human triple negative breast cancer transferred to zebrafish (Press release, Kancera, APR 22, 2016, View Source;releaseID=1138564 [SID:1234511316]). The experiments showed that Kancera’s small molecule ROR inhibitors are able to both reduce tumor size and metastases (spread) of this aggressive tumor form. Further, Kancera reports that the company´s PFKFB3 inhibitors are active in the same model of triple negative breast cancer and that a patent application has been filed covering the discovery that PFKFB3 inhibitors enhance the effect of radiation treatment.
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Kancera has previously reported that a new generation of ROR inhibitors (e.g. the compound KAN0440550) have been developed and these show a high level of efficacy and selectivity against cancer cells compared with healthy cells at the same time as they reach a concentration in the blood after oral administration that is expected to be sufficient to achieve efficacy against several cancers such as lymphoma and solid tumors. Kancera has now examined the effect of a representative of this new generation of ROR inhibitors against solid tumor in a disease model based on a human triple negative breast cancer* implanted and studied in zebrafish. The results show that a three day treatment with a ROR inhibitor results in both reduced tumor growth and reduced metastasis (spread). The study also shows that KAN0440550 is well tolerated at the effective concentration of the compound. KAN0440550 and related ROR inhibitors are now being tested against solid cancers and lymphomas in preclinical disease models for the selection of a candidate drug complementary to KAN0439834 which is a compound that is more suited for effect against leukemia.
Kancera´s PFKFB3 inhibitor (KAN0438757) has previously been shown to be effective against the same form of breast cancer model as the ROR inhibitors above *. An additional zebrafish study verified the effect of Kancera’s PFKFB3 inhibitor in monotherapy (treatment with substance without combining it with another therapy). Kancera’s PFKFB3 inhibitor was well tolerated at the active concentration of the compound. Kancera has previously reported a discovery, made together with Professor Thomas Helleday’s research team at the Karolinska Institute, that treatment with Kancera´sPFKFB3 inhibitor enhances the effect of radiation on cancer cells in laboratory studies. This discovery has now been claimed in the United States by complementing the company’s earlier patent application which protects the PFKFB3-inhibiting compounds. Kancera is the owner also of this new patent application.
* Triple negative since three drug targets are missing due to genetic changes which makes it especially difficult to treat.
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 PFKFB3 project
By blocking mechanisms which enable the cancer cells to adapt to periods of oxygen deprivation, possibilities open for new treatment strategies. Kancera’s project is based on a specific inhibition of the enzyme PFKFB3 resulting in a decreased metabolism in cancer cells, and decreased cell growth. In addition, research shows that PFKFB3 is involved in the regulation of both angiogenesis and division of cells, two critical processes that contribute to tumor growth. PFKFB3 is more common in oxygen-deficient tumor tissue compared to healthy tissue, which makes a targeted effect therapy with fewer side effects than traditional chemotherapy possible. Inhibition of PFKFB3 is expected to starve and weaken the tumor cells by reducing their glycolysis and cell division. This is a way to overcome the current problems of tumor resistance to radiation and chemotherapy. Kancera’s PFKFB3 inhibitors have also been shown to prevent DNA repair in cancer cells following e.g. radiation treatment.