Research Program: Risk Reduction, Early Detection, Chrysotile Carcinogenesis and Novel Immunologic Therapies
November 9, 2006
Overview of the Punch Worthington Research (PWR) Lab “Labor Outreach” Agenda
Find best agent for reducing cancer risk in high-risk, asbestos exposed
workers.
Develop affordable, friendly cancer detection test (exhaled breath or blood).
Fine tune promising chronic maintenance therapies (interleukin, anti-angiogenics,
interferon alpha) to delay tumor recurrence.
Recruit eligible workers (10+ years exposure, beginning 1968 or before)
for inclusion in web-based electronic database for risk reduction and other
clinical trials.
Outline of PWR Lab Labor Union Outreach Program
I Prevention
a. Rationale. Malignant pleural mesothelioma (MPM) has a known long latency or "precancerous" period between the time of exposure to the carcinogen (substance that causes the cancer), which in the case of MPM is asbestos, and the time that clinically apparent cancer actually develops. Typically, this time period is 20-50 years. During this crucial phase, changes in the chest lining ("pleura") cells are occurring slowly and directly lead to the development of cancer. The rapidity with which MPM develops presumably depends on a number of factors, such as the type and amount of asbestos exposure, individual genetics, and possible co-carcinogens. During this long latency stage, a golden opportunity exists to interrupt the progression to cancer in people known to be at high risk (people with significant asbestos exposure). This approach has already been successful in developing prevention strategies in colon cancer, cervical cancer, and even breast cancer and holds the greatest promise for significantly altering the lives of patients at risk for MPM.
b. Plan. In order to take maximum advantage of the long latency phase in the development of MPM, a two pronged effort is planned.
1) First, a clinical program will be developed immediately to test promising agents currently clinically available. Many of these agents are specific inhibitors of inflammation, a process that is thought to be critical to the development of MPM. Some candidate agents include indomethacin, a non-selective non-steroidal anti-inflammatory agent, celecoxib (Celebrex®), a COX-2 selective non-steroidal anti-inflammatory agent, as well as others. In order to capture all relevant clinical and recruit patients for participation in clinical trials, PHLBI will more fully develop our existing database system into an asbestos workers electronic registry. We will be recruiting eligible subjects through the Asbestos Workers Union, as well as affiliates, with an emphasis on patients residing on the West Coast. Exposed workers will be able to provide exposure and health data through a confidential web-based portal.
2) Secondly, a laboratory science program will be fostered to study the mechanism of neoplastic induction over time in MPM and to identify targeted strategies for future study and development. As part of this program, an orthotopic (i.e., pleural) animal model (syngeneic or genetically altered, i.e., knockout animals) will be fully characterized using tumors arising from asbestos exposure. With a better understanding of how asbestos induces MPM, improved strategies will potentially be identified and become available for not only prevention but for treatment of this deadly disease as well.
II. Early Detection
a. Rationale. Detection of cancer at an early "stage" is thought to be helpful in any malignancy. This approach has led to the development of screening tests for a variety of cancers, including mammograms for breast cancer, stool occult blood, CEA measurement, and colonoscopy for colorectal carcinoma, PSA measurement for prostate cancer, and possibly chest x-rays or CT scans for lung cancer. Along these lines, early detection for MPM is theoretically desirable.
b. Plan. MPM, however, is thought to be a diffuse disease from essentially its earliest beginnings and has no satisfactory imaging test. Therefore, an early detection program will be a high priority with a strong emphasis in the development of an early detection method. One such protocol is currently in development which will seek to identify any tumor markers in exhaled breath or blood serum of high risk individuals. This clinical research program is now awaiting funding. The breathing test is particularly exciting as this has already been used and validated as a concept in lung cancer as well as other diseases. Other possible early detection techniques require collection of tissue and/or blood specimens for analysis. A comprehensive protocol to accomplish this is currently being evaluated.
III. Treatment
a. Rationale. MPM does not have many reasonable treatment options, although combinations of surgery, radiation, and chemotherapy/ immunotherapy offer the most optimal survival. The lack of a standard of care is partly due to the erroneous application of a short-term, "hit-or-miss" strategy with cancer care. In patients with other solid tumors, survival curves have been extended by using a two-pronged strategy that begins with an "acute" intervention and is then followed by a "chronic" maintenance phase. We have been pioneers in the development of maintenance strategies to prevent recurrent cancer or even progression of known cancer disease by the use of daily maintenance therapies.
b.
Plan. Treatment of newly diagnosed MPM, in the past, has centered around
the use of surgery, chemotherapy and radiation. We plan to aggressively develop
novel treatment strategies. One such therapy is intra-operative treatment
with an interleukin-4 (IL-4) immunotoxin. Furthermore, an active research
program is being instituted to develop novel therapy options such as treatment
with compounds that modify the ELR- CXC chemokine cascade that has been shown
to be important in the development of new blood vessels that are responsible
for "feeding" the tumor (angiogenesis). This strategy also will
be tested in vitro (in a Petri dish system) with other promising therapies
to determine the optimal combination of therapies for future clinical trials.
Furthermore, the addition of maintenance therapies has been a rationale that
is long overdue. In the same way that hypertension (high blood pressure)
and diabetes (high blood glucose) require constant supervision to control
the abnormalities, thereby supporting long-term survival, MPM requires similar
maintenance strategies. One such strategy involves long-term maintenance
interferon alpha therapy. We have been using interferon alpha in selected
patients for over five years with some patients living longer than five years
and a median survival of 38 months in patients who have received such therapy.
Contact:
Dr. Robert Cameron; (310) 794-7333; email: rcameron@phlbi.orgRoger G. Worthington, Esq., (800) 831-9399; email: rworthington@phlbi.org