Childhood Cancer Research at theMedical University of South CarolinaSeptember 12, 2014 Jacqueline M Kraveka, D.O.Associate ProfessorDirector, Pediatric Oncology Research LaboratoryDepartment of PediatricsDivision of Hematology-Oncology

1. Childhood Cancer Research at the
Medical University of South Carolina
September 12, 2014
Jacqueline M Kraveka, D.O.
Associate Professor
Director, Pediatric Oncology Research Laboratory
Department of Pediatrics
Division of Hematology-Oncology

2. 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.

3. 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.

4. 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.

5. 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.

6. Facts About Childhood Cancer
• 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.

7. 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.

8. 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
54
19
59
53
86
45
65 65
42
50
73
90
64
75 76
97
85
71
64
67 67
90
100
80
60
40
20
0
% Survuval
Relative 5 Year Survival Rates
1975-1977
2002-2008

9. Treatment Efficacy has Improved but
Survivors Pay a High Price in Side Effects
Efficacy has Improved… …but side effects
5 Year Survival Rates
Adapted from http://www.acco.org/Information/AboutChildhoodCancer/ChildhoodCancerStatistics.aspx and
Seer Cancer Statistics Review 1975-2010
20%
84%
100%
80%
60%
40%
20%
0%
1950-1954 2002-2008
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

10. • 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

11. • 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

12. • 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

13. Investment in Childhood
Cancer Funding
Federal Funding for Pediatric Cancer Research
is less than the cost of 1 Boeing 787 Dreamliner!

14. 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.

15. 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.

16. 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.

17. 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.

18. Pediatric Oncology Research Laboratory
• 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 tumors
b) Sphingolipid based therapeutics
c) Novel drug delivery systems

19. 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.

20. 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

21. 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.

22. 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

23. 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

24. 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!

25. 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!

26. Allocation of Funds
Laboratory 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

27. Thank you for your generous
support !!!
Dr. Li Li Dr. Mehrdad Rahmaniyan
Dr. Amr Qudeimat