We are interested in using molecular imaging and molecular diagnostic tools to evaluate the development of metastatic disease in humans and in preclinical models. Toward this end, we evaluate clinical, biological and imaging data from patients with cervical cancer treated with radiotherapy with or without the administration of concurrent chemotherapy. All of these patients have undergone pre and post treatment imaging with positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG). Clinical data indicates that residual or new sites of FDG uptake present on the post-treatment PET are predictive of poor survival outcome. We performed a large scale gene expression profiling study from pretreatment biopsies from cervical cancer patients treated with definitive chemoradiation and evaluated for posttreatment FDG uptake by PET. Gene Set Enrichment Analysis (GSEA) identified alterations in expression of genes from the PI3K/Akt pathway that were associated with residual or new sites of abnormal FDG uptake on the posttreatment PET. To confirm our results at the protein level, a tissue microarray was constructed from 164 pretreatment cervical cancer biopsies. Immunohistochemistry using a phospho-specific Akt anti body (pS473) confirmed pAkt as a biomarker for poor prognosis in patients with cervical cancer treated with chemoradiation.
To follow up on these results, we are interrogating the Akt signaling pathway further using cervix cancer cell lines and patient derived tumor samples. We are determining the isoform specific expression pattern of Akt and screening for mutations in upstream regulators of Akt signaling. We are testing downstream components of the Akt signaling pathway implicated in the regulation of glucose uptake. We hypothesize that increased expression of pAkt contributes to increased glucose uptake in cervical cancer cells and this is linked to increased cell survival after chemoradiation. We hypothesize that silencing of Akt may enhance the sensitivity of cervical cancer cells the radiation and/or chemotherapy. To test this, we are performing cell survival, apoptosis and glucose uptake assays with and without Akt silencing after treatment with radiation +/- cisplatin chemotherapy. These experiments are designed to generate preclinical data in support of the use of Akt inhibition as a novel therapeutic strategy for cervical cancer. We are developing a preclinical bioluminescent model of metastatic cervical cancer that will allow for evaluation of investigational imaging and therapeutic reagents.
Cervical cancer is unique in that these are no well established serum or tumor biomarkers associated with diagnosis, prognosis or treatment monitoring. Additional projects in the lab include identification and evaluation of candidate biomarkers associated with cervical cancer outcome. This includes whole transcriptome and genomic sequencing of patient-derived samples and correlation of those results with postreatment outcome.
Finally, metastasis is a complex biologic process that allows tumor cells to escape the primary site, invade the circulation and establish new tumors at distant sites. Recent work has established a role for bone marrow-derived hematopoietic progenitor cells (HPCs) in this process. HPCs that express VEGFR1 and the integrin a4b1 arrive at sites of metastasis and form a receptive environment for tumor cells known as the premetastatic niche. We are currently collaborating with Carolyn Anderson’s laboratory in the preclinical evaluation of 64Cu-CB-TE2A-LLP2A, an investigational reagent for PET imaging that targets the a4b1 receptor. We are exploring novel imaging methods for tracking tumor cell and HPC migration in vivo using bioluminescence and genetically engineered mice. We are testing the role of a4 expression in the development of distant metastatic disease using the Tie2-Cre a4f/f mouse.
Gynecologic oncology, thyroid oncology, radiation oncology.