Blog

Chasing Away Childhood Cancer

An Update from Dr. Kraveka

 

Dear Friends and Supporters of Chase After a Cure,

In this season of giving and celebration, I wanted to take a moment to thank you all for your generous support. As you may be aware Whitney Ringler founded Chase After a Cure in 2009, after her son Chase was diagnosed with stage IV high risk neuroblastoma.

Neuroblastoma is a cancer of the sympathetic nervous system. It is 3rd most common cancer overall and the most common solid tumor of infancy. Most children are diagnosed before their 4th birthday. It has one of the lowest survival rates of all childhood cancers. About half of children diagnosed with neuroblastoma will have “high risk” disease that has spread to other sites in their body. The survival rate for children with “high risk” neuroblastoma is less than 50%. This means that about half of these children will relapse. Currently there are no effective cures for relapse. New treatments and approaches are urgently needed.

Funds raised by Chase After a Cure have been instrumental to my research efforts at the Medical University of South Carolina (MUSC) Children’s Hospital. I am a pediatric oncologist who treats patients and also has research lab. My research lab is the only one in South Carolina that is dedicated to pediatric cancer research. I focus mainly on neuroblastoma and on identifying and developing new treatments for this deadly disease. The goal our research is to develop new treatments for children that will be more effective and have fewer side effects.

My laboratory research focuses on sphingolipid based therapeutics for pediatric cancers, particularly neuroblastoma. Sphingolipids make up cell membranes and play important roles in cancer cell growth. Targeting sphingolipid metabolism has been shown to be a novel and effective method of cancer cell destruction. Work from my laboratory has identified “novel” biologic functions for a type of sphingolipid called dihydroceramide We propose that increasing dihydroceramide levels in cancer cells, with compounds that we have developed, will lead to improved cure rates.

Our current research projects include:
• Identification of new biomarkers in neuroblastoma
• Developing novel inhibitors to the dihydroceramide desaturase enzyme (DEGS-­‐1) for pediatric cancer therapy
• Studying the role ceramide sythases in high-­‐risk neuroblastoma
• Studying the regulation on MYCN oncogene by sphingolipids and retinoid compounds
• Studying sphingosine kinase inhibitors in pediatric cancers

Sphingolipid targeted therapies have great potential for pediatric cancer therapy because they:
• Can be combined with existing chemotherapeutic agents to improve clinical outcomes.
• Can help overcome drug resistance.
• Can enhance responses to radiation therapy
• Can inhibit tumor metastases, migration, invasion, and angiogenesis.
• Can have fewer side effects than conventional therapies.

I also have ongoing collaborations with several scientists:
1. Dr. Zdzislaw M. Szulc in Department of Biochemistry and Molecular Biology at MUSC. He is synthesizing novel lipid based enzyme inhibitors that we are testing in neuroblastoma.
2. Dr. Charles Smith at Apogee Biotechnology Corporation. We are testing his oral Sphingosine Kinase 2 inhibitor in pediatric cancers. Results thus far are very encouraging and plans are underway for a national Phase I pediatric trial for solid tumors using this compound.
3. Dr. Frank Alexis in the Bioengineering Department at Clemson University. We are collaborating on testing nanoparticle delivery of drugs in neuroblastoma. This approach is expected to increase the effectiveness of the drugs, while at the same time decreasing their side effects.
4. Dr. Duska Separovic in the Department of Pharmaceutical Sciences at Wayne State University. We are collaborating on the role of dihydroceramide desaturase in photodynamic therapy for solid tumors.

Our lab is a member of the Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC). The NMTRC is a group of 25 universities and children’s hospitals, headquartered at Helen Devos Children’s Hospital in Grand Rapids, MI that offer a nationwide network of childhood cancer clinical trials. These trials are based on the research from a group of closely collaborating investigators who are linked with laboratory programs developing novel therapies for high-­risk neuroblastoma and medulloblastoma.

This consortium’s mission is to create a national collaborative effort of researchers, oncologists and family advocates to bring forward new therapies for children with relapsed neuroblastoma and medulloblastoma with the goal of improving the quality of life and survival of children with neuroblastoma and medulloblastoma. Through the NMTRC, we have a network in place in which we can take the discoveries made in our lab directly to patients. Your support has enabled us to open a number of clinical trials for our patients in South Carolina. Your support has helped defray the costs of running these trials and have partially funded a coordinator for these trials. Patients from across the state have participated in these trials.

Clinical trials in pediatric cancer continue to be a key factor in progress toward better treatment and prognosis. The significant advances in the success of treatment of pediatric cancer have come, in part, from the high participation rate of patients in such studies. Clinical trials have as their primary goal the improvement of future treatment. Clinical cancer research involves testing new agents, combinations and treatment programs in an orderly series of steps or phases.

As an NMTRC member, I have been involved in the development of 11 NMTRC clinical trials for patients with relapsed neuroblastoma. I was involved in the first FDA approved pediatric personalized medicine trial for children with relapsed neuroblastoma. We have now expanded on this approach to include all pediatric cancers in 2 subsequent trials. I was the Rare Tumor Study Chair of the NMTRC clinical trial, NMTRC 008: A Feasibility Trial using Molecular-­‐Guided Therapy for the Treatment of Patients with Relapsed and Refractory Childhood Cancer. Our current trial (NMTRC 009) is a multicenter study, which is evaluating the ability of using RNA sequencing analysis of a child’s tumor along with DNA mutation panels to predict individual therapies for the patient. These studies outline an approach by which we can use our expanding knowledge of the individual genetics of tumors to understand the mechanisms, which cause tumors to grow. This knowledge is then used to identify specific targeted therapies for each patient.

We are also excited to have the FIRST neuroblastoma chemoprevention trial open at MUSC. This trial, NMTRC003: A Phase II Preventative Trial of DFMO as a Single Agent in Patients With High Risk Neuroblastoma in Remission. This innovative trial will evaluate an experimental oral drug (DFMO) in high-­‐risk neuroblastoma patients whom are in remission. It is hoped that treatment with DFMO will prevent neuroblastoma patients from relapsing. Currently ~ 50% of children with high-­‐risk neuroblastoma will relapse after completion of upfront therapy. As of today we have enrolled 6 patients in South Carolina. Preliminary results from the DFMO trial are very promising.

In December 2015, we are excited to open a new trial for newly diagnosed patients, NMTRC 012: PEDS-­‐PLAN -­‐ Pediatric Precision Laboratory Advanced Neuroblastoma Therapy. A Pilot Study Using Molecular-­‐Guided Therapy along with Induction Chemotherapy for Subjects with Newly Diagnosed High-­‐Risk Neuroblastoma. I am the vice-­‐chair of this study. This breakthrough study will incorporate molecular profiling of the patient’s tumor at diagnosis, and add a targeted agent to the standard treatment of children with newly diagnosed high-­‐risk neuroblastoma. It is hoped that this approach will further improve cure rates for these children.

Phase I trials are a critical first step in the study of novel cancer therapeutic approaches. These trials evaluate a new drug to determine its maximum tolerable dose; toxicities (side effects) (including the dose limiting toxicity); and the metabolism and elimination of the agent (pharmacokinetics). Some early evidence of anti-­‐tumor activity is also sought. Participants have usually failed known active treatment or have a tumor for which there is no known active agent. Phase I trials may include not only first trials of a new agent in pediatric medicine but also new schedules or combinations of agents. Currently, pediatric phase I trials are only offered in a few locations across the United States, dramatically limiting access for our patients due to the financial struggles and other difficulties of being so far away from home. Our goal is to provide the patients in South Carolina with the cutting-­‐edge therapies and treatments they need, so that they don’t have to travel out of state.

We also have two phase I trials opening in 2016:
• NMTRC 010: A Phase I/II Trial of DFMO in Combination with Bortezomib in Patients with Relapsed or Refractory Neuroblastoma
• NMTRC 011: A Phase I Trial of Tolcapone alone and in Combination with Oxaliplatin in Patients with Relapsed or Refractory Neuroblastoma or Medulloblastoma

In 2015 I became a member of the NMTRC Executive Committee and the NMTRC Scientific Committee. The Executive Committee provides oversight, advice, and strategic planning for the consortium. The Executive Committee’s responsibilities include:
• Oversight of the Consortium’s institutional and individual membership.
• Approval of new protocols in conjunction with the Scientific Committee.
• Approval of scientific collaborations undertaken by the Consortium.

Your support since 2009 for Chase After a Cure has resulted in 13 publications, over 400 citations, 5 invited presentations and 21 oral and poster presentations and national and international meetings. We generated preliminary data that supported our proposals for peer-­‐ reviewed funding from the National Childhood Cancer Foundation, Hyundai Hope on Wheels, Rally Foundation for Pediatric Cancer Research, and the St. Baldrick’s Foundation. Your funds have helped us:
• Support and fund the work of 3 scientists in the lab
• Purchase key equipment for our lab such as:
o EVOS fluorescent microscope used to visualize drug treatments,
o BioTek Synergy H1 Multi-­‐Mode Plate Reader used for cancer cell death assays, enzyme assays, cancer cell drug discovery experiments
o BioRad CFX96 Touch Real-­‐Time PCR thermal cycler used for cancer cell gene expression analysis
o Biorad ChemiDoc Touch Gel and Western Blot imaging system used for protein expression analysis in cancer cells
• Subsidize the cost of lab experiments and consumables such as reagents, pipettes, tissue culture plates.
• Improve access to cutting edge clinical trials for the children of South Carolina.

• Partially fund a coordinator for our NMTRC trials.

Thank you again for your generosity. Our research program would cease to exist without your support. Only research can find a cure for cancer. Our research offers hope for a cure.

Sincerely,

Jacqueline M. Kraveka, D.O. Associate Professor of Pediatrics
Director, Pediatric Oncology Research Laboratory