Drug repurposer

It’s a good thing when a class of drugs for one disease can be used to treat another. Such repurposing can hasten a new therapy’s journey to the clinic, since it has already passed tests of its stability and safety.

Inhibitors of the family of signaling proteins named Janus kinases (JAKs) are a case in point. Approved by the US and other drug agencies for the treatment of a form of leukemia and for autoimmune diseases, this class of drugs is now also being tested in people diagnosed with lymphoma and other advanced malignancies. Ludwig Melbourne’s Matthias Ernst hopes to add another cancer to his team’s therapeutic portfolio. In 2014, he and his colleagues showed that JAK inhibitors shrink colon tumors in mice. If these findings hold true, the researchers could quickly begin testing their effects in patients.

In that regard, it certainly helps that Ernst is the inaugural scientific director of the Olivia Newton-John Cancer Research Institute (ONJCRI) in Melbourne. The ONJCRI, which opened its doors last year and is the successor to the Ludwig Melbourne-Austin Branch, is functionally integrated with the Olivia Newton-John Cancer and Wellness Centre, which is one of Melbourne’s three major cancer hospitals and runs more than 60 clinical trials per year. “We are all in the same building, with hospital beds for cancer patients on one side and basic research done on the other,” says Ernst. The ONJCRI will focus much of its effort on basic and early translational research, though its clinician-scientists will also be running many phase 1 and 2 clinical trials through the Olivia Newton-John Cancer and Wellness Centre. “This is what everybody talks about when they think about comprehensive cancer centers,” Ernst says.

Busting bowel cancer

Ernst’s studies exploiting JAK inhibitors stem from a combination of long-standing interests, including cellular mediators called cytokines and their involvement in bowel, or colorectal, cancer, the second-leading cause of cancer-related deaths in most industrialized countries. Researchers have identified some of the key molecular drivers of this disease. For instance, about 80% of colon cancers involve mutations in a tumor suppressor gene called adenomatous polyposis coli (APC). These mutations drive uncontrolled cell division and tumor growth.

Unfortunately, this knowledge has not yet led to the development of clinically approved drugs that target tumors with APC mutations. One reason for this is that experimental drugs that interfere with the signaling pathway that involves APC can stop tumor growth, but they can also damage normal colon tissue. This is because they stop the ordered cell division that keeps the self-renewing organ healthy and prevents conditions like colitis.

JAK inhibitors may offer a route around this problem: Ernst showed in 2013 that their targets are important for the growth of colitis-associated colon cancers. In their new study, Ernst and his colleagues demonstrated in mice that JAK inhibitors could also stop much more common forms of sporadic colon cancer that arise from APC mutations. Better yet, they could do so without damaging the healthy parts of the intestines.

Ernst’s team is conducting further tests in mouse models and following up on preliminary studies suggesting that the drugs may be useful in other cancers, such as those of the lung. JAKs are activated in response to inflammation, which is a hallmark of the cellular environment of many tumor types.

Forging partnerships

Ernst’s studies leverage a network of academic and pharmaceutical partners, including the Melbourne-based biopharmaceutical company CSL. He is working with CSL on a parallel approach to treating bowel cancer. This approach targets interleukin-11, a secreted molecule for intercellular communication that sends its signal into target cells through the JAK pathway. In previous studies, Ernst has shown that antagonists of the interleukin-11 receptor, which have been developed by CSL, can foil bowel cancer in mice.

Ernst has also helped build productive partnerships between some of the institutions that support research at the ONJCRI, which include Ludwig, La Trobe University, the State Government of Victoria and the National Health and Medical Research Council of Australia. “This is a very exciting environment,” he says. “It is well suited to where my research is going.”

REFERENCES

Phesse TJ, Buchert M, Stuart E, Flanagan DJ, Faux M, Afshar-Sterle S, Walker F, Zhang HH, Nowell CJ, Jorissen R, Tan CW, Hirokawa Y, Eissmann MF, Poh AR, Malaterre J, Pearson HB, Kirsch DG, Provero P, Poli V, Ramsay RG, Sieber O, Burgess AW, Huszar D, Vincan E, Ernst M. Partial inhibition of gp130-Jak-Stat3 signaling prevents Wnt-b-catenin-mediated intestinal tumor growth and regeneration. Sci Signal. 2014 Sep 30;7(345):ra92. doi:10.1126/scisignal.2005411.

Stuart E, Buchert M, Putoczki T, Thiem S, Farid R, Elzer J, Huszar D, Waring PM, Phesse TJ, Ernst M. Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice. Mol Cancer Ther. 2014 Feb;13(2):468-74. doi: 10.1158/1535-7163.MCT-13-0583-T. Epub 2014 Jan 7.

Putoczki TL, Thiem S, Loving A, Busuttil RA, Wilson NJ, Ziegler PK, Nguyen PM, Preaudet A, Farid R, Edwards KM, Boglev Y, Luwor RB, Jarnicki A, Horst D, Boussioutas A, Heath JK, Sieber OM, Pleines I, Kile BT, Nash A, Greten FR, McKenzie BS, Ernst M. Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell. 2013 Aug 12;24(2):257-71. doi: 10.1016/j.ccr.2013.06.017.