We have several ongoing research projects:
here to view the SimmonCooper Cancer Institute ongoing clinical
Basic Research in Dr. Krishna Rao's laboratory:
- Breast Cancer is the
most common malignancy among women in North America, accounting
for 32% of all new cancer diagnosis and 15% of all cancer related
deaths each year. Although early stage breast cancer can be successfully
treated, later stages of the disease carry higher mortality rates.
Our laboratory has investigated mammary spindle cell carcinoma.
Spindle cell carcinoma of the breast is a rare but aggressive variant
of breast cancer that frequently metastasizes and is associated
with a poor prognosis. It rarely expresses the estrogen receptor,
progesterone receptor, or the erbB2 protein, limiting therapeutic
options with hormonal agents or transtuzumab. Additionally, it is
poorly responsive to standard chemotherapeutic agents. We have analyzed
a spindle cell carcinoma line developed by introduction of defined
genetic elements and have shown loss of rab25 as a last step prior
to transformation. Our preliminary data indicate that:
- Loss of rab25 expression correlates with tumorigenicity of mammary cell lines with active ras pathways. The lines tested included both spindle and epithelial cell lines, suggesting that rab25 is important in a variety of breast cancer histologies.
- Loss of rab25 expression significantly correlates with the transformation of human mammary epithelial cells in vivo.
of rab25 in breast tumor cells significantly suppresses cell
proliferation and invasiveness.
Our hypothesis is that rab25 rescues the tumorigenic effect of ras in breast cancer. The specific aims are (1) to clarify the suppressor activity of rab25 and its relationship to ras, (2) to examine the in vivo effects of rab25 expression on tumor formation, and (3) to examine the status and relationship between ras mutation and rab25 expression in human breast cancer patients. The goal of this project is to understand the role of rab25 in the pathogenesis of breast cancer. Rab25 represents a novel class of agents, tumorigenesis mediators, which modulate the aggressive behavior of cancers. Understanding the etiology and pathogenesis of breast cancer is a key step towards improving therapy for patients afflicted with this disease.
Rao K, Bryant E, McDougall JK. (2003). Production of spindle cell carcinoma by transduction of H-Ras 61L into immortalized primary human mammary epithelial cells. Cancer Letters, 201: 79-88
JiMing Cheng, Ming Ding, Ahmed Aribi, Prabodh Shah, Krishna Rao. Loss of Rab25 expression in breast cancer. Int J Cancer. 2006 Jun 15;118(12):2957-64.
Rao K, Ozge Alper, Kent Opheim, George Bonnet, Kristine Wolfe, Eileen Bryant, Shiobhan Larrivee, Peggy Porter, James McDougall Cytogenetic characterization and H-ras associated transformation of immortalized human mammary epithelial cells. Cancer Cell International 2006, 6:15 (26 May 2006).
- Our other area of focus is head and neck cancer. Smaller head and neck SCCA lesions (stage T1-T2) are effectively treated either by surgical excision or irradiation whereas more advanced disease (stage III-IV) is treated with combined surgery and XRT or chemoradiation. Although the combination of IV polychemotherapy and irradiation has been shown to have potent anti-tumor effects, it only results in a local control rate of 50-60% and overall survival of 30-50%. High dose intraarterial chemotherapy is a novel approach to locally advanced head and neck SCCA that results in higher rates of local control, reduced treatment toxicity, and improved survival as compared to historical controls. RADPLAT, a specific concomitant chemoradiation protocol for head and neck cancer, capitalizes on the CDDP-neutralizing agent sodium thiosulfate and its pharmacokinetic properties, so that enormous concentrations of cisplatin can be infused directly into large head and neck tumors through a targeted intraarterial approach. In a phase I study, it was determined that cisplatin could be safely administered to patients with advanced and recurrent head and neck cancer at a dose intensity of 150 mg/m2/week. Tarceva is a compound that antagonizes the EGF receptor and is currently approved to treat lung carcinomas. Our hypothesis is that head and neck cancers are resistant to apoptosis from DNA damage induced by radiation and chemotherapy. This resistance is mediated by EGFR overexpression which results in downstream activation of cell survival signals, such as AKT, and may be overcome when tarceva is co-administerd with intraarterial chemotherapy and radiation. We are about to open a phase II study of supradose intraarterial cisplatin with tarceva, and the scope of the proposed trial which will include all upper aerodigestive tract (oral cavity, oropharynx, hypopharynx, and larynx) squamous cell carcinomas. We hypothesize that the combination of tarceva and RADPLAT will be a synergistic. We will be collecting tumor specimens during the study and analyzing samples to extent of apoptosis and proliferation with this novel therapeutic combination.