In recent years, the advances in our understanding of the molecular basis of cancer have led to the potential for rational drug development based on the molecular changes of specific tumors. The prime example of this kind of dramatic breakthrough in the treatment of cancer is the success of the drug Gleevec in the treatment of chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). Promising preliminary results have also been produced by a number of other targeted molecular therapies. However, unlike CML and GIST, which have only one molecular abnormality that is blocked by Gleevec, malignant brain tumors have multiple genetic abnormalities. Therefore, it is likely that combinations of targeted molecular drugs will be more effective than single drugs in these tumors.
Another area of research is the development of drugs that block a tumor's ability to make new blood vessels, a process termed angiogenesis. There is a large laboratory effort studying new drugs that block angiogenesis and combining these drugs with radiation therapy and chemotherapy to increase their effectiveness. Dr. Kesari is involved in clinical trials of several drugs (AZD2171, sorafenib, enzastaurin, avastin and VEGF-Trap, CT-322) that block the main cause of angiogenesis in brain tumors. Preliminary results have been very exciting with ~50% of patients showing responses.
MOLECULARLY TARGETED TUMOR THERAPY INITIATIVE
Unraveling the Genetic Basis of Brain Tumors through Family Ties
Dr. Kesari has observed that some of his brain tumor patients have other family members with brain tumors or other cancers. Although rare, studying these patients' blood and tumor samples may help to uncover the genetic causes of brain tumors. Thus, we hope to be able to incorporate this information into future research programs
Tumor cells stably expressing GFP (green); blood vessels stained with PE-labeled antibody anti-vWF (red). Staining was performed by immunohistochemistry on a coronal section from mouse brain harvested 15 days after tumor cell implantation.
In addition, hydrocephalus is a common problem associated with a majority of these patients (and also patients with primary brain tumors) that is under recognized and poorly understood, and clearly affects function and quality of life. Oftentimes this is associated with spread of the cancer cells into the CSF fluid. We are developing novel surgical treatment approaches to treat the hydrocephalus, while simultaneously allowing us to also directly instill chemotherapy into the CSF. Early experience is very promising with improvements in neurological function, survival, and QOL in our patients.
Intra-tumoral Blood Vessels
Improving the Treatment of CNS complications of Systemic Cancer
Please see these publications relating to our work on identification of paraneoplastic antibodies and treatments of these rare syndromes.
Identification of novel paraneoplastic antibodies
Neurotoxicity is a common problem in neuro-oncology from chemotherapy-induced peripheral neuropathy to radiation-induced leukoencephalopathy yet we do not have good preventative guidelines or treatment measures for these problems. In our lab, we are working on the detailed mechanisms of neurological injury so that we can identify new drugs to prevent damage. In the clinic, we are using and studying various drugs to alleviate symptoms of both brain damage from radiation and neuropathy from chemotherapies.
(Image Credit: Cellworks Group, Inc.)
At the Translational Neuro-Oncology Laboratories, we are using innovative in silico approaches to optimize therapy for brain cancers. As part of this Initiative, we recently published a paper that demonstrates the use of a predictive model to identify targeted drugs that will be most effective against a patient's tumor - based on the genomic profile of that tumor.
We are also using networks-based analyses to identify important intracellular molecules that can serve as targets for glioblastoma or as biomarkers for therapy.
COMPUTATIONAL MODELING AND NETWORK PHARMACOLOGY INITIATIVE
TRANSLATIONAL RESEARCH IN NEURO-ONCOLOGY
An important focus of research is to characterize the molecular changes, which occur in each individual brain tumor and understand the genes that cause these tumors and enable them to become resistant to treatment with radiation therapy and chemotherapy. The ultimate goal is to determine the unique molecular characteristics of each person's tumor and select the most appropriate targeted treatment based on these molecular abnormalities. This tailoring of treatment to each person gives us the greatest chance of achieving a cure. The genomic and proteomic technology that allows us to characterize the molecular changes in each person's tumor is available now.
Molecular Profiling ot Tumors
We perform dynamic susceptibility-contrast (DSC) MRI scans on patients with brain tumors. In addition, we also use quantitative FLAIR and restriction spectrum imaging (RSI) studies to assess effects on edema and tumor cellularity. Our ultimate goal as part of this initiative us to assess imaging biomarkers as early markers of response to therapy.
We are working on identifying and validating new biomarkers in CSF, blood and imaging. These biomarkers can act as surrogates for pharmacodynamic data and can help stratify patients for different targeted therapeutics. In addition, biomarkers can help identify new targets for drug development.
Spread to the brain from breast, lung, and hematological cancers is an increasingly common problem due to better local treatments of the primary cancer. There is clearly a need to better understand the biological underpinnings of this problem and to develop novel CNS directed approaches to prevent brain metastases or to optimally treat at presentation. We are developing methods to detect this earlier with novel imaging modalities and through analysis of cerebrospinal fluid (CSF) and blood proteins.
CANCER STEM CELLS INITIATIVE
Understanding Genetic Basis of Treatment
Restriction Spectrum Imaging
TRANSLATIONAL NEURO-ONCOLOGY LABORATORIES (TNOL)
Because Dr. Kesari treats patients with brain tumors, he has keen insight into treatment response in patients. By investigating in detail a patient that responded to Gleevec (a PDGFR inhibitor), Dr. Kesari has a found a genetic marker that may allow one to predict response to treatment. We are actively working to further confirm these findings. We are also taking similar approach to validate functional role of genomic aberrations of EGFR as predictors of sensitivity/resistance of glioblastoma to EGFR tyrosine kinase inhibitors (EGFR-TKI). Such insights poise Dr. Kesari and his team in discovering genetic biomarkers of response that will allow us to tailor treatments for brain tumors in a personalized manner. These discoveries has already enabled Dr. Kesari to initiate a prospective clinical trial for PDGFR inhibitors in biomarker-enriched high-grade glioma patients.
There is increasing evidence that brain tumors may arise from abnormal stem cells in the brain. We are working with a large number of colleagues to understand the role of stem cells in the development of brain tumors. Understanding the function of stem cells will allow us to specifically target these cells to treat brain tumors. Dr Kesari and colleagues has discovered that Olig genes play a crucial role in allowing stem cells to become gliomas; therapies directed against these genes may represent a novel way to treat malignant gliomas.
Immunotherapy for other cancers has show impressive responses and long-term remissions with a real possibility of curing patients. We are testing various immunological approaches in laboratory for glioblastoma and other brain cancers. As well, we have open clinical trials and new protocols in development with various companies on new drugs.
NOVEL IMAGING INITIATIVE
SANTOSH KESARI, MD, PhD
BIOMARKER DEVELOPMENT INITIATIVE