December 2016/January 2017

Researchers Find Compelling Preclinical Evidence for High-Risk Leukemia Therapies

If there is some small bright spot in getting a diagnosis of childhood cancer, it is that acute lymphoblastic leukemia (ALL), the most common form of leukemia in children, has one of the highest cure rates of all childhood cancers. Yet families may struggle to see that bright spot if they learn that their child’s ALL is in the genetic subgroup known as Philadelphia-like B-cell lymphoblastic leukemia (Ph-like ALL), named for the disease biology’s similarity to cancers caused by the famous Philadelphia chromosome mutation.

Although Ph-like ALL was first thought to be a rare subset of ALL cases, it is now known to account for 10 to 20 percent of B-cell ALL occurring in children and adolescents and nearly 30 percent of the disease in young adults. Patients with Ph-like ALL have a very high risk of relapse and poor responses to usual chemotherapy. After relapse, the prognosis for ALL is dim.

Researchers at Children’s Hospital of Philadelphia are working to restore the bright light of hope for children, adolescents, and young adults with Ph-like ALL by evaluating new drugs that could potentially better target leukemia cells than existing therapies. CHOP pediatric oncologist Sarah Tasian, MD, recently led a study of several drug compounds that act on signaling pathways previously implicated in Ph-like ALL. The results, published in the journal Blood, showed potent efficacy of one individual drug and several drug combinations in preclinical models of the disease.

“There’s been a tremendous amount of work across the world defining the genetics of Ph-like ALL, but fewer studies have focused on the functional implications of those genetic mutations,” said Dr. Tasian, who is also an assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. Her lab has long been interested in both understanding and therapeutically targeting the functional changes in leukemia cells caused by Ph-like ALL mutations.

Several years ago, Dr. Tasian and her collaborators at CHOP and other institutions identified molecular signaling pathways that were activated in Ph-like ALL. They have recently turned their attention to further experiments with one of these, the PI3 kinase pathway, because newer drugs have emerged to target this pathway.

“There has been a lot of progress with ‘next-gen’ PI3 kinase pathway inhibitors that have only been explored in adult cancers, primarily solid tumors,” Dr. Tasian said. “They haven’t really been tested in leukemia and particularly not in pediatrics.”

The study used immune system-deficient mice engrafted with leukemia cells from children with Ph-like ALL to measure individual effects of four drugs that target different steps of the PI3 kinase pathway. One drug, gedatolisib, has a dual mechanism of action and simultaneously targets both PI3 kinase and mTOR proteins in the pathway. The researchers also tested the PI3 kinase inhibitors in combination with drugs that target other signaling pathways.

Dr. Tasian was surprised to find that gedatolisib worked particularly well, even without being combined with other drugs. It not only shut down leukemia proliferation, but it also actively killed the cancer cells. This single drug nearly cured the mice of their leukemias, which was an unexpected result; in patients, multiple types of chemotherapy drugs are usually combined to achieve cure. In addition, the mice appeared to tolerate the drug well without losing weight or having changes in their healthy blood cell levels. These were particularly favorable results because adult patients treated with PI3 kinase inhibitors for other types of cancer have reported numerous toxic side effects.

“We were really excited to see the efficacy, but we’re also very happy to see the tolerability,” Dr. Tasian said. “You want a cure, but not at a great cost.”

In addition to these findings about gedatolisib as a stand-alone therapy, Dr. Tasian and colleagues found that combining drugs to target the PI3 kinase pathway and another signaling pathway simultaneously even more potently inhibited leukemia growth in the mice and was superior to the effects of individual drugs.

Because this was the first time researchers have evaluated “next-gen” PI3 kinase inhibitors in depth for pediatric Ph-like ALL, more preclinical data will be necessary before these drugs can be considered for clinical testing in patients. Even though many important steps remain before patients can potentially see an impact of this work, Dr. Tasian describes the initial findings as “compelling.”

“We need very robust preclinical data to convince investigators and our industry colleagues to take the leap to clinical trials, particularly in children,” she said. “A constant challenge for us in pediatric oncology is access to cutting-edge cancer drugs and the ability to partner with pharmaceutical companies for testing in children.”

Fortunately, Dr. Tasian and her colleagues in the Children’s Oncology Group (COG) have a strong track record of making that happen. At the same time that they identified activation of PI3 kinase signaling in Ph-like ALL a few years ago, they also found that the JAK signaling pathway is similarly hyperactivated. They previously tested a JAK inhibitor in a COG Phase 1 clinical trial and found it to be well tolerated in children with relapsed cancers. Dr. Tasian now chairs a COG Phase 2 clinical trial testing a JAK inhibitor and chemotherapy specifically in children with Ph-like ALL.

The speed of discoveries along this road, from genetic discoveries to mechanistic molecular understanding, to preclinical and ultimately clinical testing, has been fueled by the dual supports of funding and scientific collaboration. Early support from childhood cancer foundations including the Alex’s Lemonade Stand Foundation and the Rally Foundation allowed Dr. Tasian to generate pilot data and secure additional funding from the National Institutes of Health to expand and bring the ideas to fruition. At the same time, collaboration and mentorship through COG and at CHOP have been vital, including the input of co-authors of the new study who include Stephan Grupp, MD, PhD; David Teachey, MD; and Stephen Hunger, MD. In this environment, Dr. Tasian has taken findings first identified during her post-doctoral fellowship at the University of California, San Francisco with Mignon Loh, MD, through to chairing a major COG clinical trial in less than a decade.

“My goal with all of this work is to get innovative therapies to children as quickly as we possibly can,” Dr. Tasian said. “Being at CHOP in such a translational environment is amazing in its emphasis not just upon scientific discovery, but also asking, ‘How do we move that along?’ We are unequivocally committed to providing the best possible care for children.”

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