A Slice of Life: The Search for Variation in Brain Tumors

For Dr. Archana Gopalan the search for better cancer treatment begins with a paper-thin slice of tissue. "If we can keep the tumor tissue intact, we have everything that encompasses the tumor, changes in immune system cells, proteins, molecules present around the tumor, and then treat them with the drugs we use in clinics."  Dr. Gopalan plans to examine the differences within brain tumors, seeking to unravel the mystery of why glioblastoma is so resistant to conventional cancer treatment. 

Most cancer tumors are similar throughout– they look and behave the same, and treatment is based on the type of cells found in that the tumor.  However, in this type of brain cancer (glioblastoma), the cells look and behave very differently – they are heterogeneous.  It is speculated that cancer cell heterogeneity directly leads to tumors that do not respond to treatment, but there is not a lot of experimental evidence. 

Despite decades of research and development, highly malignant cancers such as Glioblastoma multiforme (GBM) remain incurable. GBM is characterized by highly mixed cancer cell appearances (cancer cell heterogeneity), among different patients and even within the same patient tumor. Recent studies suggest that cancer cell heterogeneity is a common feature of malignant cancers and it reflects not only different stages of maturation in individual cells but also different genetic changes that occurred in different groups (subclones) of cancer cells (cancer evolution). 

 

It is speculated that cancer cell heterogeneity directly contributes to the emergence of therapy resistant tumors and therapy failures in the clinic. While there is strong evidence for genetic heterogeneity in the same patient tumor, there is little to no experimental evidence that cellular heterogeneity directly leads to emergence of therapy resistant tumors. The goal of this proposal is to test this idea by exploiting a tumor slice culture system we developed recently to map and evaluate responses of different GBM subclones within the same patient tumor to TMZ (Temozolomide) plus radiation treatment, standard care for GBMs.

Specific Aims and Rationale

Emerging deep sequencing analyses of human cancers indicate that significant degree of cancer cell heterogeneity exists both among different patients (intra-tumoral) as well as within the same patient (inter-tumoral). This intra- and inter-tumoral heterogeneity, indicated by presence of cells with different genomic compositions and consequently different gene expression patterns, is likely to contribute to differential therapy response by different subclones.

For example, currently, selection of targeted therapies is based on the most dominant mutations or pathway activation detected in the bulk tumor tissue; however, if there were subclones that do not have the same mutation or pathway activation, then they would escape the targeted therapy and generate resistant tumors. Cancer cell heterogeneity may also contribute to therapy resistance to cytotoxic drugs, due to differential levels of DNA damage pathway activation or mutations in other essential signaling pathways. For GBMs, there is strong evidence that genetic/epigenetic status of the patient tumor plays a strong role in determining therapy response. For example, TMZ treatment for GBM is effective only in patients with methylated (silenced) MGMT expression (1). Therefore, we will exploit our ability to sample and test small regions of the same tumor and computationally reconstruct relative positions of tumor subclones using ex vivo tumor slice culture system. The specific aim of this project is to test our hypothesis that different subclones of GBM cells within the same patient tumor are differentially sensitive to TMZ + IR treatment.

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Organization: 
The Jackson Laboratory
Researcher: 
Archana Gopalan, Ph.D
Grant Amount Given: 
$50,000
Year Issued: 
2014
Period: 
Annual
Grant Category: 
Research
Types of Cancer: 
Brain
Grant Duration: 
1 Year Pilot Grant

Maine Cancer Foundation Grants to this Organization:

Year Program Amount Category Organization
2014 Genetic Testing for Primary Care Providers: Case-based Web Modules $49,220 Education The Jackson Laboratory
2014 A Secondary Syndrome: Acute Myeloid Leukemia $50,000 Research The Jackson Laboratory
2014 Are Micro RNAs the Key to Stopping Lung Cancer? $50,000 Research The Jackson Laboratory
2014 Mouse Models for Acute Myeloid Leukemia $169,834 Research The Jackson Laboratory
2014 A Slice of Life: The Search for Variation in Brain Tumors $50,000 Research The Jackson Laboratory
2013 Defining Susceptibility To Transformation By Epigenetic Landscape $49,999 Research The Jackson Laboratory
2013 Assessing Therapeutic Potential of a New Drug ICG-001 in Glioblastoma $50,000 Research The Jackson Laboratory
2013 The Maine Triple-Negative Breast Cancer Study $212,601 Research The Jackson Laboratory
2013 Development of Optimized Ex Vivo Organotypic Slice Culture Systems $164,686 Research The Jackson Laboratory
2012 FoxC2 Function in glioma stem cells and Vasculature $84,000 Research The Jackson Laboratory
2012 New Models for Lung Cancer Research $199,036 Research The Jackson Laboratory
2012 Online CME Course $27,600 Education The Jackson Laboratory
2011 Imaging Glicoma Stem Cell Dynamics in Vivo $90,000 Research The Jackson Laboratory
2010 MicroRNA Expression during Lung Tumor Progression $90,000 Research The Jackson Laboratory
2010 Genetic Chemotherapy: Inducing Leukemia and Lymphoma Cell Self Destruction $67,500 Research The Jackson Laboratory
2010 Notch Signaling in Medulloblastoma Initiation and Cancer Stem Cell Maintenance $90,000 Research The Jackson Laboratory
2009 Validating S100A6 as a Novel Marker and Potential Therapeutic Target of Brain Cancer Stem Cells $80,000 Research The Jackson Laboratory
2008 Development Genomics of Lung Cancer $79,524 Research The Jackson Laboratory
2008 Homologous Recombination Factor XRCC2 in B-Cell Genome Stability and Tumor Supression $79,696 Research The Jackson Laboratory
2006 Chromatin Reorganization in Pro-B Cell Lymphoma Nuclei $74,180 Research The Jackson Laboratory
2006 The Role of Src Kinases in Regulation of Stem Cell Survival in CML $75,000 Research The Jackson Laboratory
2005 A Gene Expression Study for the Hormone Independent Growth Transition of Ovarian Cancer Cells in vivo $20,000 Research The Jackson Laboratory
2004 Malignant Ovarian Granulose Cell Teumorigenesis $37,165 Research The Jackson Laboratory
2003 Parent-of-Origin Genetics in a Model of Ovarian Ganulosa Cell Tumorigenesis $35,500 Research The Jackson Laboratory