BACKGROUND AND CHALLENGES OF A RARE CANCER - SARCOMA

Soft tissue sarcomas are a diversifi ed group of more than 50 types of rare, malignant tumors that develop from tissues such as fat, muscles, or nerves. A particularly aggressive subtype which develops from tissues surrounding the nerves is malignant peripheral nerve sheath tumor (MPNST). A distinguishing characteristic of MPNST is the propensity to metastasize or spread to other sites, predominately to the lungs. Chemotherapy and radiation are the only treatment options for metastatic MPNST and unfortunately, tumors that have spread to distant sites in the body are insensitive to these therapies.

Due to the limited treatment options for metastatic MPNST, patients face a dismal prognosis with a five year overall survival range of 30 - 50%. The main impediment to the development of new and effective therapeutic approaches for this deadly cancer is the lack of understanding at the molecular level of what genes or proteins have gone haywire to initiate uncontrolled cell growth.

THE OPPORTUNITY FOR NEW TREATMENTS

Dr. Dina Lev, NFCR Project Director

To advance MPNST research, Dr. Lev is combining clinical and biologic resources. Her team has assembled a retrospective MPNST clinical database of former patients treated at MDACC during the last 15 years. The clinical history of patients' disease, combined with analysis of associated variables, such as tumor size and surgical outcome, has provided an effective tool to help physicians develop a prognosis for their MPNST patients. To expand this clinically-based
resource, Dr. Lev's team developed a complementary biological information resource and linked it with the annotated clinical database. A tissue microarray (or a collection of samples) from preserved tumor biopsies of both former and current patients was created in which antibodies can be used to detect the protein mediators of MPNST. Correlation of the microarray data with the clinical data provides the capability to identify known diagnostic indicators and to discover the molecular players of MPNST. These newly-identified molecular markers may form the basis for development of new treatment options for MPNST.

Dr. Lev's research team may have identified a marker of metastatic MPNST. The intricate Ras kinase protein (Ras) plays a key role in normal cell growth; but one of the few abnormalities known in MPNST is a DNA mutation which overproduces Ras - resulting in uncontrolled cell growth and tumors. mTOR and AKT are two of many proteins that interact closely with Ras and may play a role in tumor development when Ras is overproduced in MPNST patients.  Using the newest tissue microarray technology, Dr. Lev's team discovered that AKT protein plays a more direct role than mTOR, and it is only overproduced in metastatic tumor samples but not in primary tumor samples. This suggests that drugs designed specifi cally to block AKT proteins may be able to stop MPNST metastasis and provide hope for these patients.

Finally, Dr. Lev will next use cutting edge siRNA technologies to identify all proteins that associate with Ras in MPNST cell lines and block the function of those proteins to confirm the key proteins that stop uncontrolled cell growth. These studies have signifi cant potential to identify novel therapeutic targets for MPNST researchers, and that means new opportunities to develop drugs that will fight MPNST.

Dr. Wei Zhang, NFCR Project Director

To search for genes associated with MPNST, Dr. Zhang and his team are using an expanded high throughput genomic screen. Rare cancers, such as Sarcoma and subtype MPNST, require a systematic study of a large number of samples to identify new genetic abnormalities and proteins that may be involved with the disease process. To expand this endeavor to the necessary scale, Dr. Zhang has formed two collaborations.

His team works closely with Dr. Lev sharing their MPNST samples at MDACC. He has also established an international
collaboration with Dr. Jilong Yang at the Tianjin Cancer Institute and Hospital (TMUCIH) in Tianjin, China, which houses the NFCR-TMUCIH Joint Tissue Bank. NFCR and TMUCIH jointly support the Tumor Tissue Bank - one of the largest comprehensive sarcoma resources in China. These high impact collaborations provide Dr. Zhang's research team with the
necessary large sample size to conduct a genome-wide screen for new genes gone haywire in MPNST.

An expert in tumor genetic profi ling, Dr. Zhang is searching for mutations in DNA of MPNST patients which cause certain genes to be overexpressed or to be underexpressed - both scenarios can result in uncontrolled cell growth. By comparing samples from patients with MPNST or other sarcomas to those from patients with benign tumors, Dr. Zhang is using cutting edge research (including microRNA chips) to identify new genes and proteins that may be candidates for the development of targeted therapy for MPNST. If the genes and proteins they identify are targets of known and established drugs, a clinical trial for MPNST patients will be initiated quickly.

NEXT STEPS: HOW YOU CAN HELP
The Hope Fund for Sarcoma Research is a donor-advised fund established by Ken and Marianne Bouldin, in partnership with NFCR. The Bouldins founded the Hope Fund after their daughter, Jennifer, survived MPNST. The goals of this restricted fund are twofold: to raise awareness of MPNST and to gather and engage the brightest minds in the international scientifi c community in order to identify new biomarkers for early diagnosis and improved therapies that offer hope to
MPNST patients and their families.  To learn more and support the Hope Fund, click here.