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Research in the Lake laboratory focuses on cancer and infectious disease. In the area of cancer, we recently reported the discovery of a peptide that is present in plasma from patients with pancreatic cancer, but not in plasma from normal donors. This peptide maps back to a parent protein called quiescein sulfhydryl oxidase 1 (QSOX1). We then demonstrated that QSOX1 protein is over-expressed in pancreatic tumor cells, but not in adjacent stroma or infiltrating lymphocytes. Subsequent studies examining the spectrum of expression of QSOX1 in other tumor types demonstrated that it is over-expressed in nearly every histological tumor type tested so far including murine tumor cell lines such as 4T1 (breast cancer), 3LL (lung cancer) and B16 (melanoma). Very little is known about the tumor biology of QSOX1. To answer the question of why tumor cells over-express this protein, we suppressed production of QSOX1 using shRNA. We found that QSOX1 plays an important role in tumor cell growth and invasion leading to metastasis. In a human tumor xenograft-murine model, we observed a 77% reduction in tumor growth for tumors in which QSOX1 protein production was suppressed. The hypothesis that has emerged from these studies is that the QSOX1 enzyme is a target for anti-neoplastic drugs or gene therapy approaches. We are also studying the tumor biology of QSOX1 and its potential as a biomarker in a range of cancers including pancreatic, lung, bladder, breast and melanoma.
Tumor-specific staining from a patient with PDA. Left arrow indicates absence of staining in normal duct. Right arrow indicates tumor in ductal epithelium.
In another tumor type, Multiple Myeloma, the Lake laboratory is collaborating with Mayo Clinic scientists in the area of individualized medicine. Over the past decade, unprecedented advances have been made in the treatment of multiple myeloma (MM). Patients can be selected to receive therapeutics that are most likely to result in maximal cytoreduction for their disease. In fact, most patients now achieve complete responses such that there is no evidence of disease using current diagnostic assays. Unfortunately, many patients who were complete responders ultimately relapse, even after autologous stem cell transplantation. A major problem is that our treatments have advanced beyond our ability to detect residual disease; current diagnostic and monitoring assays have simply not kept pace with MM therapeutics. We are addressing this problem by bringing highly sensitive and accurate mass spectrometry techniques into the MM diagnostic and monitoring area.
M-protein is an immunoglobulin (Ig) or Ig light chain that is a unique and natural tumor marker, individualized for each patient. The bonus is that M-protein Igs are secreted, making them ideal blood-based biomarkers. Although 90% of Ig sequences are nearly identical, the antigen-binding regions, or complementarity determining regions (CDRs) of Igs are unique and specific for each patients' malignant MM tumor. We taking advantage of the sensitivity and accuracy of mass spectrometry to to identify and detect M-protein fragments in serum of MM patients at time of diagnosis as well as after or during treatment. If successful, our method will detect M-protein at levels 2 to 3 orders of magnitude more sensitively than current methods allow. Our goal is to advance detection of M-protein as a marker of MM such that it complements new therapies so that clinical responses can be more accurately correlated with M-protein levels.
Finally, the Lake laboratory is studying an infectious disease important to the people of Arizona. Coccidioidomycosis or "Valley Fever" (VF) is caused by the fungus Coccidioides sp., which lives in soils of the southwestern US and San Juaquin Valley in California. When soil is disturbed, humans and animals can inhale fungal spores that germinate in the lung to produce a respiratory infection that ranges in severity from mild to life-threatening, and can easily be misdiagnosed as community acquired pneumonia. Because VF is caused by a fungus, it is important to differentiate VF patients from those who may have viral or bacterial pneumonia. Currently available tests to distinguish VF from other community acquired pneumoniae, are based on the ability of patients to mount an antibody response to the fungus. Unfortunately, the antibody-based tests are inadequate for many patients because it may take weeks to months to develop such an antibody response (leading to delayed diagnosis), and many immunocompromised patients are unable to mount any antibody response at all. Therefore a blood test to detect coccidioidal proteins would allow a definitive diagnosis to be made even if serology is negative. We are identifying a panel of coccidioidal peptides and proteins that will provide a definitive diagnosis for physicians to treat patients suffering from Valley Fever.