Four Projects, One Goal: Curing Childhood Cancer

Curing childhood cancers is certainly no easy task, but researchers at The Children’s Hospital of Philadelphia are not deterred by a big challenge. Recent grants from CURE Childhood Cancer are supporting that work for four investigators at CHOP pursuing creative approaches to achieve this vision.

Developing Tiny Tumor Drug Deliverers

Many cancer treatments have harmful side effects when they act on healthy tissues in addition to cancer cells. A team led by Garrett M. Brodeur, MD, director of the Cancer Predisposition Program at CHOP, and funded by a CURE grant, is seeking ways to increase drug delivery to the tumors to improve drugs’ effectiveness while reducing their toxicity.

Their method uses tiny nanoparticles as delivery vehicles. Nanoparticles are a promising way to get drugs into tumors because tumor blood vessels are leaky, and the nanoparticles can enter the tumor much more easily than normal tissues.

“By increasing drug delivery to tumors by one or two orders of magnitude, we can achieve dramatically better anti-tumor effects while simultaneously decreasing total drug exposure to patients,” Dr. Brodeur said.

Dr. Brodeur’s team, including Co-Principal Investigator Michael Chorny, PhD, is developing and optimizing nanoparticles to carry and release two different targeted drugs into tumors. They will test the two nanoparticle-carried drugs in vitro in models of high-risk neuroblastoma, alone and in combination. The nanoparticles and drugs they are using could be used for other high-risk tumors, including sarcomas and brain tumors.

Understanding a Growth-Stopping Drug Candidate

A compound called JQ1 could potentially force cancer cells to lose their cancer identity and reprogram them as normal cells. That is one hypothesis that Margaret M. Chou, PhD, and her team will test in their study of the compound, which they have previously found to kill cancer cells in vitro and to curb tumor growth in animal models of the devastating bone cancer Ewing sarcoma. Their experiments are designed to find the mechanism of how JQ1 shuts down a pivotal protein involved in this disease.

"My laboratory is so grateful for CURE's support of our work,” Dr. Chou said. “Ewing sarcoma is an incredibly difficult pediatric cancer to treat, and we hope that studies enabled by this funding will pave the way for the development of novel therapeutics."

Finding Role of Mitochondria in Treatment Response

A team led by CHOP pediatric oncologist Richard Aplenc, MD, PhD, MSCE, received a second year of funding from CURE to continue its investigation of the role of mitochondrial DNA in the risks of relapse and infection in patients with acute myeloid leukemia (AML).

Mitochondria, the organelles inside cells that provide the body’s energy, have their own distinct genome, which Dr. Aplenc’s team will sequence from several hundred patients enrolled in a clinical trial for AML. Recent studies in adult cancers have indicated mitochondrial genes might play a role in different chemotherapy outcomes among patients, but researchers have not yet established such a connection in pediatric cancers.

Seeking Molecular Mechanisms of Resistance to Treatment

With a second year of CURE funding, CHOP pediatric oncologist Michael Hogarty, MD, is continuing another line of research on the role of mitochondria in pediatric cancer. Dr. Hogarty’s team is testing a hypothesis, supported by their preliminary data, that resistance to treatment in neuroblastoma tumors is caused in part by changes in the combined functioning of the cells’ mitochondria and another organelle, the endoplasmic reticulum (ER). If you think of the mitochondria as the powerhouse of the cell, then the ER would be the assembly line where proteins are built.

They believe that problems with the signaling mechanism between the ER and mitochondria could drive treatment resistance in cancer cells. They plan to validate whether alterations of this ER-mitochondria signaling are indeed predictive of cancer becoming resistant, and to understand the nature of the connections between alterations and resistance.

“With ongoing funding from this CURE award we are uncovering important clues into how cancer cells become resistant to available treatments,” Dr. Hogarty said. “This remains the single greatest barrier to improving cancer outcomes.”

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