The ROR project
Small molecules against leukemia. Studies in several animal species have made it possible to calculate how Kancera’s drug candidate KAN0439834 may function in the body of a patient. The calculations show that Kancera’s drug candidate is likely to possess characteristics that provide a desired effect against cancer in humans with an oral therapy 2-3 times per day.
Recent studies, performed in cooperation with the Karolinska Institute, support that Kancera’s candidate drug is effective against both leukemic cells circulating in the blood and leukemic cells that have invaded the lymph nodes in humans.
Other recently completed studies of clinical samples from leukemia patients underscore that ROR inhibitors mainly target the white blood cells causing cancer while the healthy white blood cells, including T cells, are spared. These results are of significance for the ability of patients to counteract infections and also open up the possibility to combine ROR inhibitors with the new generation of immuno-stimulating cancer drugs that are currently being developed. The effect of these drugs requires healthy white blood cells. Taken together, these results provide a basis for the planning of the safety studies required before any clinical trials.
Small molecules against solid tumors. Kancera is developing a new group of small molecule ROR inhibitors that are chemically similar to the drug candidate KAN0439834 but are smaller in size and show a three-fold higher killing effect in vitro against cancer cells from solid tumors such as pancreatic cancer. Thereby Kancera now takes steps towards addressing one of the cancers that are most difficult to treat.
ROR vaccine. Studies in 2014 showed that certain peptide sequences found on the outside of the ROR protein gave an immune response in rat that selectively killed the leukemia cells from patients. The effect of this immune response against leukemia cells was similar to the effect that can be achieved with ROR-targeted antibodies against leukemia cells, but significantly weaker than the effect of Kancera’s small molecules. Further studies have shown that certain leukemia patients have the ability to immunologically react against ROR by generating antibodies against the parts of the ROR protein (ROR-peptides) which Kancera previously identified as potential starting points for vaccine development. Thus, these patients' immune system reacts spontaneously on peptide sequences overlapping with Kancera’s selected vaccine candidates. These observations prompt Kancera to start a new vaccine study to test methods to enhance the immune response to selected ROR-peptides in order to evaluate if a sufficiently strong immune response can be generated against cancer or if small molecules ROR inhibitors are to be preferred. This work will continue in 2015.
The PFKFB3 project
The collaboration with Professor Thomas Helleday’s research group at SciLifeLab has led to a surprising discovery showing that Kancera’s PFKFB3 inhibitor KAN0437757 prevents cancer cells to repair the DNA following treatment with e.g. radiation. When the cancer cell is unable to repair its DNA it will die. This opens up for a new type of treatment of radiation resistant cancer, which combines the currently available DNA-damaging treatments (chemotherapy or radiation) with a PFKFB3 inhibitor. This new treatment concept is supported by studies in cancer cells showing that PFKFB3 contributes to the ability of the cancer to resist treatment. Thus, a PFKFB3 inhibitor could have the function to amplify the effect of cancer treatments such as radiation treatment. Additional basic research studies are necessary in order to fully understand the capabilities and limitations of a cancer treatment that combines Kancera’s PFKFB3 inhibitors and radiation. However, it is clear that this new discovery provides strong reasons to examine the possibilities of an improved cancer treatment.
The results from the study of Kancera’s PFKFB3 inhibitors will be presented by Dr. Nina Sheppard at the scientific meeting Tomas Lindahl Conference on DNA Repair in Oslo with the title "Inhibition of the glycolytic enzyme PFKFB3 kills cancer cells by modulating DNA repair".
The HDAC6 project
In December 2014 Kancera reported that the company’s HDAC6 inhibitors act selectively through an additional mechanism via a not yet disclosed target protein (Target 2), which may contribute to the inhibition of cancer cell survival. In order to evaluate this potential united action, Kancera has now designed and synthesized compounds that only inhibit HDAC6 and compounds that inhibit both HDAC6 and Target 2. When the patent application for the HDAC6 inhibitor that was filed last year enters the international phase in May 2015 it will provide protection for these new compounds.
In 2015, Kancera, in collaboration with Dr Li-Sophie Zhao Rathje at the Karolinska Institute, has performed laboratory studies demonstrating that Kancera’s HDAC6 inhibitors selectively counteract the migration of the cells that normally surround tumors*. This finding indicates that Kancera’s HDAC6 inhibitors could make it more difficult for these cells to migrate to the tumor and create a surrounding protection against medical treatment and the body’s immune system.
* So-called cancer-associated fibroblasts
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.
About the HDAC6 project
Histone deacetylases (HDACs) are primarily involved in removing acetyl groups from the so-called histones and thereby affect how our genes are stored and activated in the cell nucleus. Some HDACs also affect the cell function outside the cell nucleus. HDAC6 belongs to this group of HDACs with a major biological role in the regulation of the cancer cell´s ability to migrate and to form metastases. The use of HDAC inhibitors in the treatment of cancer patients has so far yielded promising results, but has been limited due to severe side effects. For this reason, the pharmaceutical industry is now looking for more selective inhibitors of individual HDAC enzymes. Kancera´s discovery of selective HDAC6 inhibitors may provide a solution on how health care could take advantage of the anti-cancer effects of HDAC inhibitors without causing the patient severe side effects.
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 10 people. Kancera shares are traded on NASDAQ OMX First North and the number of shareholders with at least 500 shares was around 5500 as of March 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 additional information, please contact:
Thomas Olin, CEO: Tel +46 735 20 40 01
Karolinska Institutet Science Park
SE 171 48 Solna,Sweden
Please visit the company’s web www.kancera.com