South Carolina Childhood Cancer Research Lab Presentation

Childhood Cancer Research at theMedical University of South Carolina

September 12, 2014

Jacqueline M Kraveka, D.O.Associate Professor

Director, Pediatric Oncology Research LaboratoryDepartment of Pediatrics

Division of Hematology-Oncology

MUSC

• Founded in 1824 as the first school of medicine in the southeastern U.S., the Medical University of South Carolina is now the core of the state’s largest medical complex.

• A freestanding academic health center, MUSC is the only tertiary/ quaternary care referral center in South Carolina for a statewide population of about 4.3 million people.

• MUSC is the lead biomedical research institution in Health Sciences South Carolina, a statewide consortium to facilitate efficiency and speed in developing, testing and bringing health interventions and therapies to widespread use.

MUSC Children’s Hospital

• The MUSC Children’s Hospital is dedicated to enhancing the health of children throughout South Carolina and to providing an environment that supports excellence in pediatric patient care, teaching, and research.

• MUSC Children's Hospital is the largest and most comprehensive pediatric medical center in South Carolina.

• Our health system covers the state with an extensive network of physicians, health care professionals and services – all dedicated to children. MUSC Children’s Hospital has earned top rankings from US News and World Report, Child magazine and American Health Magazine.

Hollings Cancer Center

• In spring 2009, Hollings Cancer Center was named a designated cancer center by the National Cancer Institute (NCI). Hollings is South Carolina's only NCI-designated cancer center -- and one of only 65 in the country.

• This distinction identifies cancer centers offering the most advanced research and clinical trails for cancer. NCI-designated cancer centers are a major source in developing new cancer treatments and more effective approaches to cancer prevention and diagnosis. These cancer research centers deliver medical advances to patients and their families, educate health care professionals and the public, and reach out to underserved populations.

Facts About Childhood Cancer

Childhood Cancer is not just one disease. It is made up of a dozen of types and countless subtypes.

Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, Bunin GR (eds). Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program, Bethesda, MD, 1999.

• Childhood cancer is the #1 cause of death from disease in children in the US, more than from asthma, diabetes, cystic fibrosis, congenital anomalies, and pediatric AIDS combined. It is the 2nd leading cause of death in children overall, after automobile accidents.

• ~ 12,500 children are diagnosed with cancer per year in the US.

• More than 40,000 children and adolescents are currently in treatment.

• Each and every school day, 46 children, or more than two full classrooms of kids, are diagnosed with cancer in the United States alone.

• 1 in every 4 elementary schools has a child with cancer.

• The average age of cancer diagnosis is 6 years old.

Facts About Childhood Cancer

• 1 in 300 children will be diagnosed with cancer before age 20.

• Each year over 2,000 children die, and over 40,000 are in treatment.

• The average high school has 2 students who are survivors.

• 3 out of 5 survivors will have long lasting chronic conditions from treatment.

• The causes of childhood cancer are unknown.

• Today, up to 84% of the children with cancer can be cured, yet some forms of childhood cancer have proven so resistant to treatment that, in spite of research, a cure is illusive.

• Cancer in childhood occurs regularly, randomly and spares no ethnic group, socioeconomic class, or geographic region.

Facts About Childhood Cancer

Improvements in Survival Have Not Been Consistent Across Childhood Cancers

Adapted from http://www.acco.org/Information/AboutChildhoodCancer/ChildhoodCancerStatistics.aspx and Seer Cancer Statistics Review 1975-2010

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Treatment Efficacy has Improved but Survivors Pay a High Price in Side Effects

Adapted from http://www.acco.org/Information/AboutChildhoodCancer/ChildhoodCancerStatistics.aspx and Seer Cancer Statistics Review 1975-2010

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Efficacy has Improved… …but side effects are increasingly damaging

• Secondary cancers• Heart Damage• Kidney Damage• Lung Damage• Hearing Loss• Infertility• Alterations in growth and development• Impaired cognitive abilities and psycho-

social impact

Two-thirds of survivors will experience at least one of these side effects

• Solid tumor cancer that originates in the nerve tissue of the neck, chest, abdomen, or pelvis, but most commonly in the adrenal gland.

• Neuroblastoma is a common and often difficult to treat cancer.

• Neuroblastomas are the most common cancer of infancy, with an incidence rate almost double that of leukemia, during the first year of life.

• Accounts for ~15% of all childhood cancer deaths• 3rd most common pediatric cancer:

– Most commonly diagnosed cancer of infancy– Majority diagnosed under age 5.

• Neuroblastoma has one of the lowest survival rates of all pediatric cancers.

Neuroblastoma

• Over 80% of children diagnosed with neuroblastoma during infancy are alive 5 years following diagnosis.

• In contrast, for children diagnosed with neuroblastoma at age 18 months or older, the 5-year relative survival was only about 45%.

• In the United States, about 700 children are diagnosed with neuroblastoma each year. Of these ~45% with have advanced “high risk” disease.

• The survival rate of high risk children is less than 40%.

• There are few effective treatments for relapsed neuroblastoma.

Neuroblastoma Facts

Maris JM, N Engl J Med. 2010

• Solid tumor cancer arising from skeletal muscle.• ~900 children diagnosed with soft tissue sarcomas

annually, of which ~350 are RMS.• RMS is most common soft tissue sarcoma under age

14. (50% of cases) • RMS is a common and often difficult to treat cancer. • 2 main types of RMS:

– Embryonal RMS– Alveolar RMS

• Metastatic Alveolar RMS has one of the lowest survival rates of all pediatric cancers (<40% survival).

• There is essentially no curative therapy for relapsed rhabdomyosarcoma.

Rhabdomyosarcoma

Ries LAG, et al, SEER, 1999

Investment in Childhood Cancer Funding

Federal Funding for Pediatric Cancer Research is less than the cost of 1 Boeing 787 Dreamliner!

Facts on Childhood Cancer Funding

• All 12 major groups of pediatric cancers combined receive ~4% of the NCI Budget

• Cost of a Boeing 787 Dreamliner or C-17 Globemaster airplane is $218 million.

• New York Yankees Payroll ($208.8 million) was more than the amount of money allotted to pediatric cancer research.

• Only Research Cures Childhood Cancer.

Childhood Cancer Care at MUSC

• The division of pediatric hematology-oncology at MUSC offers comprehensive care for children with cancer and blood disorders. The members of the division include: Dr. Michelle Hudspeth, Dr. Jacqueline Kraveka, Dr. Shayla Bergman, Dr. Jennifer Jaroscak, Dr. Amy-Lee Bredlau, Dr. Julie Kanter and Dr. Sherron Jackson.

• There are over 70 new childhood cancer diagnoses seen annually at MUSC.

• Last year there were 4600 out-patient oncology visits and over 800 admissions to the inpatient oncology unit.

• Dr. Kraveka’s research lab in the Darby Children's Research Institute is the only laboratory the state of South Carolina dedicated to pediatric cancer research.

Childhood Cancer Care at MUSC • MUSC Children’s Hospital is the only pediatric bone marrow transplant

center in South Carolina. • We perform over 25 pediatric transplants each year.• Only ACGME Pediatric hematology-oncology fellowship program in the

state, training future pediatric oncologists. • MUSC Children’s Hospital is a member of the Children’s Oncology Group

(COG) and the Neuroblastoma Medulloblastoma Translational Research Consortium (NMTRC).

• The Children’s Oncology Group is the world’s premier pediatric cancer research collaborative. This network of more than 200 Children’s Hospitals and 8,000 healthcare professionals is dedicated to the cure of all children with cancer.

• 90% of children in North America are treated at COG institutions and enrolled on COG clinical trials. COG members have been the primary innovators in new treatments for children with cancer.

Clinical Research – NMTRC Consortium

• The consortium’s mission is to create a national collaborative effort of researchers and oncologists to bring forward new therapies for children with relapsed cancers with the goal of finding a cure for these patients.

• The consortium opened the 1st personalized medicine trial for pediatric cancer. – This study outlines 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.

• The FIRST neuroblastoma chemoprevention trial open is open at MUSC. This trial will evaluate a drug called DFMO in children whose neuroblastoma is in remission. The hope is that DFMO will prevent the neuroblastoma from coming back.

• These trials offer children new hope for a cure.

• The MUSC Pediatric Oncology Research Laboratory is the only one in the state dedicated to pediatric cancer research.

• The Lab is led by Dr. Jacqueline Kraveka, who is a pediatric oncologist.– Clinical pediatric oncologist– Researcher, Darby Children’s Research Institute– Member, Lipid Signaling in Cancer Research Group– Member, Developmental Therapeutics Group Hollings Cancer Center

• Her research focuses on developing novel therapies for the treatment of pediatric solid tumors.

• Current laboratory research projects focus on:a) Identifying novel biomarkers for pediatric solid tumorsb) Sphingolipid based therapeutics c) Novel drug delivery systems

Pediatric Oncology Research Laboratory

Translational Research at MUSC

Current laboratory research projects focus on sphingolipid based therapeutics. We are studying inhibitors to 3 key enzymes in the sphingolipid pathway:

1. Dihydroceramide Desaturase (DES-1 or DEGS-1)2. Sphingosine Kinase 2 (SphK-2)3. Ceramide Synthases

Sphingolipid targeted therapies have great potential for pediatric cancer therapy:– May be combined with existing chemotherapeutic agents and improve

clinical outcomes.– May help overcome drug resistance.– May enhance responses to radiation therapy.– May inhibit tumor migration, invasion, and angiogenesis.– Could potentially have less side effects than conventional therapies.

Overview on Sphingolipids• Sphingolipids play important roles

in signal transduction and cell regulation.

• Ceramide is a precursor for more complex sphingolipids and is generated by multiple pathways.

• Ceramide mediates cell differentiation, growth arrest, senescence, and apoptosis.

• Ceramide stimulates cancer cell differentiation.

Hannun Y A , Obeid L M J. Biol. Chem. 2011;286:27855-27862

Screening for DEGS-1 Inhibitors

• 30 different compounds were synthesized by the MUSC Lipidomics Shared Resource Facility.

• All of the compounds were lipid based sphingolipid analogues.• All were screened for DEGS-1 activity, and 6 inhibited DEGS-1

activity in tumor cells.• All inhibited cell growth. • These compounds have potential to be developed as new

targeted therapies for pediatric tumors in the future.

Why Target Sphingosine-1-Phosphate?

• Sphingosine-1-phosphate (S-1-P) – Stimulates cell proliferation – Involved in angiogenesis– Involved in inflammation

• S-1-P is generated exclusively by sphingosine kinases.

• Sphingosine kinase is an attractive target for cancer treatment.Block sphingosine kinase

Decrease S-1-P

Inhibit cell proliferation Promote apoptosis in cancer cells

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ABC294640 : A Novel Sphingosine Kinase 2 (SphK-2) Inhibitor

• ABC294640 is a novel oral SphK-2 inhibitor – inhibits growth of breast cancer,

hepatocellular carcinoma, pancreatic adenocarcinoma, & renal carcinoma

– It has not been tested in any pediatric cancers.

• It is a nonlipid, small-molecule inhibitor of SphK-2 identified from a chemical library.

• Synthesized and developed by Dr. Charles Smith at MUSC and Apogee Biotechnology, it is the FIRST orally available SphK-2 selective inhibitor.

• Currently in Phase I trial for Adults with Advanced solid tumors at MUSC.

Beljanski V. et al, J Pharmacol Exp Ther, 2010

ABC294640 : A Novel Sphingosine Kinase 2 (SphK-2) Inhibitor

• Pre-clinical studies with ABC294640 in neuroblastoma and pediatric sarcomas in the Kraveka Lab have been very promising.

• ABC294640 kills pediatric cancer cells and works well in combination with chemotherapy.

• We are currently testing the best combination of ABC294640 and chemotherapy to use in pediatric clinical trials.

• In the next few months, Apogee Biotechnology will manufacture smaller capsules for use by pediatric cancer patients.

• These studies will lay the groundwork for opening a Pediatric Phase 1 study in 2015.

• Funding from has been crucial to the success of this research!

Laboratory costs are over $175,000/yr

• Since its founding in 2009 has raised over $705,000!

• Funding has resulted in:– 12 publications – over 345 citations – 4 invited presentations – 20 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.

The MUSC Pediatric Oncology Research Lab would not exist without your support!

Allocation of FundsLaboratory costs are over $175,000/yr

• Funds have been used to:– Purchase of cutting edge laboratory equipment such as a

Fluorescent Microscope, Multimode Microplate Reader, Real-time PCR thermal cycler and Gel Imager

– Fund experiments on potential new cancer therapies – Fund Research Technician and Research Scientist's Salaries– Defray Costs of Laboratory Supplies such as reagents, flasks,

pipettes, tissue culture media, plates, enzymes– Purchase small equipment such as centrifuges and computers– Maintenance of laboratory equipment– Pay for use of lipidomics, confocal microscopy, and flow

cytometry core facilities – Support for Phase I and Phase II pediatric trials

Thank you for your generous support !!!

Dr. Amr Qudeimat

Dr. Mehrdad Rahmaniyan Dr. Li Li