By Stephen L. Lessnick, MD, PhD
By Stephen L. Lessnick, MD, PhD
The grant was for a new study by Dr. Stephen Lessnick
entitled, "Analysis of NR0B1 in Ewing's sarcoma.
"Doctors and researchers have long known that certain Ewing's sarcoma patients respond to chemotherapy, but others don't even though they have the same form of cancer," says HCI Investigator Stephen Lessnick, M.D., Ph.D. "Our research shows that GSTM4 is found in high levels among those patients where chemotherapy doesn't seem to work.
It's found in low levels in patients where chemotherapy is having a more positive effect."
The research could lead to drugs that can suppress GSTM4 in certain patients.
It also could lead to a screening test that could reveal which therapies will be most effective for patients.
"GSTM4 doesn't seem to suppress the benefits of all chemotherapy drugs, just certain ones.
A GSTM4-based test could help to identify the best therapy for each individual patient," Lessnick
By examining how EWS-FLI interacts with certain microsatellites, Lessnick
team were able to identify GSTM4.
says the next step in research is to focus on testing and treatments that may lead to better survival rates in patients.
"Personalized medicine is the next frontier in the battle against cancer," he
"We now know all cancers are not the same.
By focusing on how these proteins are expressed in individual tumors, we may soon be able to offer the treatment that will work best for each patient, and that could lead to higher cure rates," he
Lessnick is director of HCI's Center for Children's Cancer Research, and is a Jon and Karen Huntsman Presidential Professor in Cancer Research.
This research was supported by funds from the Terri Anna Perine Sarcoma Fund
, the Liddy Shriver Sarcoma Initiative
, the Sunbeam Foundation
, the Huntsman Cancer Foundation, and Alex's Lemonade Stand Foundation.
Both of the studies will be directed by Stephen Lessnick, M.D., Ph.D. at the Huntsman Cancer Institute.
The ultimate goal of the first study, "New Approaches for EWS/ETS Detection in Ewing's Sarcoma" is to improve physicians' abilities to provide an accurate diagnosis of Ewing's sarcoma to patients, to provide physicians' with molecular data which may be relevant to prognosis, and to provide a new non-invasive assay for the measurement of treatment response.
The goal of the second study, "Analysis of NR0B1 in Ewing's sarcoma" is to help to characterize the molecular mechanisms involved in Ewing's sarcoma development.
Additionally, by fully understanding these mechanisms, Dr. Lessnick
team hope to identify new therapeutic approaches for patients with this devastating disease.
proposes to adapt a newly reported methodology, LMF, towards the detection of EWS/ETS fusion transcripts.
team will first develop the system to detect any of the various EWS/ETS fusion transcripts that have been reported.
Next, they will assess the sensitivity and specificity of LMF on laboratory-based samples, and compare these results to the current gold standard, RT-PCR.
Next, they will extend their analysis to determine if the methodology can be used to detect Ewing's sarcoma cells in experimentally derived blood samples.
Finally, they will assess this methodology to an animal model of Ewing's sarcoma to mimic a likely clinical scenario.
If they are able to successfully develop this assay, and if it is more sensitive and specific than the standard RT-PCR assay, they plan to further develop this into a clinical assay through ongoing collaborations with experts in the field of molecular testing for solid tumors.
The ultimate goal of Dr. Lessnick
team is to use this assay to improve physicians' abilities to provide an accurate diagnosis to patients, to provide them with molecular data which may be relevant to prognosis, and to provide a new non-invasive assay for the measurement of treatment response.
colleagues recently developed a system to circumvent this difficulty.
By "knocking-down" endogenous EWS/FLI expression in patient-derived Ewing's sarcoma cell lines, using retroviral-mediated RNAi, they have been able to define the full complement of EWS/FLI gene targets in Ewing's sarcoma.
They have identified two of these as being critically important for tumorigenesis mediated by the fusion protein.
One of these, NR0B1, is an orphan nuclear receptor whose only prior known role is in adrenal and sexual differentiation.
Thus, they defined a new role for this factor.
now proposes to characterize the structure-function relationships present in NR0B1.
team will use a "knock-down/rescue" system to remove endogenous NR0B1 expression, and replace it with mutant forms of the protein.