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.