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Promise and Progress - Cover Story Sidebar: Personalized Approaches in Pediatric Cancer

The Time is Now: 2010-2011

Cover Story Sidebar: Personalized Approaches in Pediatric Cancer

By: Valerie Matthews Mehl
Date: November 11, 2010

Patrick Brown with Child
Patrick Brown, M.D.


Don Small
has a daunting task as director of the Kimmel Cancer Center’s Pediatric Oncology Program.  With a fraction of the money his colleagues on the adult cancer side receive and even less tumor samples to study in laboratory and clinical models, he and his team are working on behalf of the youngest victims of cancer.

There are far fewer cases of pediatric cancers than adult cancers--12,000 to 14,000 a year, compared to a half million adult cancers.  As a result, most of the large grants are directed to the more common adult cancers.  Limited research dollars coupled with limited tumor models and smaller-scale clinical trials, make this type of research arguably the most difficult in cancer.  But, if it is more difficult, it is also more rewarding.  Progress against childhood cancers, Small explains, has the potential to save decades of life.

Small was the first to identify and clone the human FLT3 gene and discover drugs that could molecularly target the mutations that cause a poor prognosis in acute myeloid leukemia (AML). Pediatric cancer expert Patrick Brown is now moving his laboratory findings to the clinic.

Infant acute lymphocytic leukemia (ALL) is rare among the rare.  While it is one of the most uncommon types of the already rare childhood cancers, in terms of years of life threatened, it is a giant.  Currently, with just 20 to 40 percent of patients surviving, it has the most dismal survival rates of any form of childhood leukemia. A new approach is desperately needed, says Brown.

Brown believes that FLT3 may be what allows the cancer to evade treatment. He is leading a national study to test a FLT3 inhibitor in ALL.   By blocking FLT3, Brown and team are hopeful that the cancer will respond to chemotherapy.  Earlier studies showed that the drug successfully turns the gene off, and now they are waiting to see if it makes a difference in treatment responses. To definitely prove its effectiveness, Brown says they will need to study 250 to 300 patients. With just 70 cases diagnosed each year in the U.S. and Canada, it could be four or five years before the trial is completed and all of the data is in. 

In the meantime, Brown is also studying a FLT3 inhibitor in children with AML who have relapsed after chemotherapy. About 20 percent of children with AML have FLT3 mutations, and Brown believes it is a key reason their cancers often return after treatment.  Another related study will test the FLT3 inhibitor treatment as the first line of therapy.

In the laboratory, Mark Levis and Keith Pratz are working on the next generation of FLT3 inhibitors.  The new drugs are more potent and selective for FLT3.  They will be the focus of a collaborative study of pediatric leukemia patients at the Kimmel Cancer Center and 13 other national cancer centers, known for their expertise in leukemia.

Right now, Brown’s goal is to make FLT3 inhibitors and chemotherapy effective enough to get all patients into a lasting remission so that they can undergo bone marrow transplant.  “One day,” Brown says, “we hope that FLT3 inhibitors and chemotherapy will cure them so they will not need a transplant.”

For pediatric patients who need bone marrow transplant to be cured, Heather Symons is working to make the option available to more patients.  In bone marrow transplant, patients have their cancerous bone marrow destroyed with high doses of chemotherapy and receive healthy, cancer-free bone marrow from a donor to replace it.  In a best-case scenario the bone marrow of the patient and donor should be a perfect match. 

Otherwise, the donor’s immune cells will view its new host as a foreign invader and begin to attack organs and tissue in a life-threatening complication known as Graft vs. Host disease (GVHD). 

A patient’s siblings offer the best chance of a perfect match, and more rarely a match can be found from an unrelated donor.  Unfortunately, many patients who need a transplant do not have a perfect match.  Even in cases where doctors are fortunate to locate an unrelated donor, the lead time it takes to search the unrelated database and perform additional testing is precious time young patients often do not have.

To combat these problems, Kimmel Cancer Center researchers Ephraim Fuchs and Leo Luznik pioneered half-matched or haploidentical bone marrow transplants. For children, a parent is always a half match and siblings often are as well, so it is extremely rare, says Symons, that a patient would not have a half match in his or her family.

Fuchs and Luznik established that half-matched bone marrow transplants can be done safely with lower-dose chemotherapy if the immune-suppressing drug cyclophosphamide is given following the transplant. Cyclophosphamide quiets the immune system enough to stave off GVHD while still allowing the donor immune cells to attack any remaining cancer cells.  Experts call this the graft vs. tumor effect. In patients who can tolerate intensive chemotherapy, Symons is conducting a clinical trial of high-dose chemotherapy prior to haploidentical transplant, followed by cyclophosphamide. Currently, this treatment is only done at the Kimmel Cancer Center, and it is helping make sure transplants are available to more patients.

The results in the clinical trial have been so favorable, with safety and toxicity comparable to matched transplants, that Symons and team are beginning to use it earlier in the treatment of leukemias and lymphomas and exploring its use in pediatric solid tumors, such as sarcomas and neuroblastoma.

The team also is investigating whether unique immunotherapies, such as giving donor lymphocytes after cyclophosphamide can help stimulate patients’ immune systems to fight against tumor cells. “The immune system becomes tolerant of tumor cells, and we have to awaken the host immune system,” Symons explains.  “When we give donor lymphocytes after cyclophosphamide, they stick around for a couple of weeks and we get a temporary attack against tumor cells.” Symons says they may be able to make lymphocyte therapy responses longer lasting by utilizing other tools to alert the immune system that tumor cells are both foreign and dangerous, a theory Fuchs has been studying for many years.

Symons would like to see these immune approaches used much earlier in cancer therapy.  “The paradigm needs to shift,” she says.  “Now, we come in with chemotherapy and everything else and use immunotherapy last.  We give six months of chemotherapy and many of the immune cells are killed off. When we then give immunotherapy, what immune system are we employing?”  Shifting to using immune-boosting therapies on the front end, says Symons, could ultimately be more beneficial to patients.

A Victory for Pediatric Patients
The Fair Pharmacology Act for Children

In the past, pediatric cancer-specific drugs were not profitable enough to enlist the support of major pharmaceutical companies.  It has been a frustrating and significant obstacle for researchers focusing on pediatric cancers.  To get drug companies on board, the FDA recently established the Fair Pharmacology Act for Children providing incentive for the pharmaceutical industry to develop and market drugs against pediatric cancers. 

The FDA will extend patents to drug companies for studies in adult cancers if they make plans to study the drugs in children as well. Patent protection for these more profitable, adult studies gives pharmaceuticals financial incentives to extend their work to pediatric cancers.

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