MESOTHELIOMA AND GENE THERAPY
keywords mesothelioma treatment, gene therapy, Iressa and mesothelioma, cancer asbestos, pleural mesothelioma malignant mesothelioma
1.1 THE EPIDERMAL GROWTH FACTOR AS A TARGET FOR MESOTHELIOMA TREATMENT
Duplication of genes is a normal process. When we lose hair or skin cells, our body replenishes them, utilizing growth factors like the epidermal growth factor or EGF. The delicate process of cell replication or multiplication can malfunction, with genes directed to continually replicate. Growth factor research aims to identify how and why genes replicate and cancers develop, and how the process can be frustrated. Scientists have identified the role of EGF in lung cancer:
1.2 MESOTHELIOMA AND EGFR EXPRESSION, LABORATORY STUDIES
The treatments are epidermal growth factor inhibitors, therapies targeting the epidermal growth factor. The first step is to demonstrate that the epidermal growth factor plays an important role in mesothelioma.
Govindan and colleagues have investigated EGFR receptor expression in mesothelioma tissue. They found that nearly 60% of samples overexpressed EGFR. www.EGFR-info.com (website devoted to EGFR research.
" A recent presentation found that asbestos prompted production of the epidermal growth factor in the laboratory. Over-expression of the epidermal growth factreceptor (EGFR) is a common finding in many solid tumors, including lung, breast and mesothelioma,and has been shown to correlate with both a poor prognosis and resistance to radiation and chemotherapy.... Recent evidence suggests that up-regulation and activation of EGFR may play a critical role in early carcinogenic events carcinogenic asbestos fibers upregulate the expression of the EGFR. Exposure of MET 5A cells to asbestos leads to the activation of nuclear factor-kB (NF-kB), a transcription factor important in the regulation of a number of genes intrinsic to inflammation, proliferation and lung defences. This study set out to examine the relationship between EGFR and NF-kB in MET 5A cells exposed to asbestos fibers The selective EGFR tyrosine kinase inhibitor, PKI166 (Novartis), inhibited the DNA binding of NF-kB mediated by crocidolite asbestos fibers.... Modulation of the asbestos-mediated EGFR/NF-kB signalling pathway may be important in the development of novel therapeutic strategiesfor both the chemoprevention and treatment of malignant mesothelioma. Faux, EGFR Induced Activation of NF-kB in Mesothelial Cells by Asbestos Is Important in Cell Survival, Proceedings of the American Association for Cancer Research, AACR, Vol. 42, March 2001.
Here are quotations from other studies:
"The upregulation of the proto-oncogene c-myc, fra-1
and egfr in fiber-induced carcinogenesis was demonstrated at different stages of
carcinogenesis." Sandhu, mRNA expression patterns in different stages
of Asbestos-induced Carcinogenesis in Rats, Carcinogenesis 2000
"The results clearly suggest that the stimulatory
effects of EGF, IGF-I and PDGF-BB...are mediated via receptor-growth factor
complexes and the protein tyrosine kinase intracellular pathway." Proteoglycans
in human malignant mesothelioma. Syrokou, Stimulation of their synthesis
induced by epidermal, insulin and platelet-derived growth factors involves
receptors with tyrosine kinase activity. Biochimie 1999
"Epidermal growth factor (EGF) is a potent mitogen
for human mesothelial cells, and autophosphorylation of the EGF receptor (EGF-R)
occurs in these cell types after exposure to asbestos, a carcinogen associated
with the development of mesothelioma. Here, the intensity and distribution of
EGF-R protein was documented by immunocytochemistry in a human mesothelial cell
line (MET5A) exposed to various concentrations of crocidolite asbestos and
man-made vitreous fibers (MMVF-10).... These studies indicate that
aggregation of EGF-R by long fibers may initiate cell signaling cascades
important in asbestos-induced mitogenesis and carcinogenesis. Pache,
Increased epidermal growth factor-receptor protein in a human mesothelial cell
line in response to long asbestos fibers, Am J Pathol 1998 Feb;152(2):333-40
"Repeated intraperitoneal injections of crocidolite
asbestos fibers induced diffuse malignant mesotheliomas in mice. A series of
mesothelial cell lines was isolated from mice at different stages in the
development of these tumors. The cell lines isolated from mice with
mesotheliomas recapitulated their growth pattern in vivo and were tumorigenic
when reinjected into syngeneic mice. Similar to human mesothelial cells,
growth of the murine cell lines was stimulated by epidermal growth factor.
Reactive mesothelial cells and mesotheliomas expressed the receptor for this
Goodglick, Growth factor responses and protooncogene expression of murine mesothelial cell lines derived from asbestos-induced mesotheliomas,
Toxicol Pathol 1997 Nov-Dec;25(6):565-73
"Asbestos fibers are human carcinogens with undefined
mechanisms of action. In studies here, we examined signal transduction events
induced by asbestos in target cells of mesothelioma and potential cell surface
origins for these cascades. Asbestos fibers, but not their nonfibrous analogues,
induced protracted phosphorylation of the mitogen-activated protein (MAP)
kinases and extracellular signal-regulated kinases (ERK) 1 and 2, and increased
kinase activity of ERK2. ERK1 and ERK2 phosphorylation and activity were
initiated by addition of exogenous epidermal growth factor (EGF) and
transforming growth factor-alpha,... MAP kinase activation by asbestos was
attenuated by suramin, which inhibits growth factor receptor interactions, or
tyrphostin AG 1478, a specific inhibitor of EGF receptor tyrosine kinase
activity (IC50 = 3 nM). Moreover, asbestos caused autophosphorylation of the EGF
receptor, an event triggering the ERK cascade. These studies are the first to
establish that a MAP kinase signal transduction pathway is initiated after
phosphorylation of a peptide growth factor receptor following exposure to
Thus, there is ample evidence of an association between the epidermal growth factor and mesothelioma. That does not explain precisely how the epidermal growth factor may be targeted for treatment, what specific receptor is involved, and whether other growth factors are equally important. It is an important first step.
1.3 IRESSA AND EPIDIMERAL GROWTH FACTOR INHIBITORS
The "new" forms of gene therapy target specific growth factors and receptors. Iressa or ZD 1839 is a promising new drug which works in part by slowing production of EGF (epidermal growth factor), and perhaps other growth factors associated with lung cancer. One writer explains how the new group of anti_EGF drugs work: "In normal cells, epidermal growth factor (EGF) regulates growth in a tightly controlled manner. In most cancers, rogue proteins send cells messages to overproduce copies of EGF, which results in relentless growthof cancer cells. The new small molecule drugs inhibit cancerous growth by disrupting the messages sent by rogue proteins inside the cell. Other new monoclonal drugs inhibit growth of tumor cells by blocking rogue proteins from attaching to EGR receptors outside the cell." Ferraro, New Ammunition in Cancer War, New York Post 5/20/01, p. 28."The epidermal growth factor receptor (EGFR) autocrine pathway contributes to a number of processes important to cancer development and progression, including cell proliferation, apoptosis, angiogenesis, and metastatic spread. The critical role the EGFR playsin cancer has led to an extensive search for selective inhibitors of the EGFR signaling pathway.... At least five blocking monoclonal antibodies have been developed against the EGFR. " Tartora, A novel approach in the treatmentof cancer: targeting the Epidermal Growth Factor Receptor, Clin Cancer Res 2001 Oct;7(10):2958-70.
" 4 of 16 nsclc patients in one trial had a partial reduction in tumor size, with another 2 having their disease stabilized. See www.egfr-info.com, (Astra-Zeneca's web site). On November 1, 2001, a press release reported, "Phase II trial results showed Iressa succeeded in shrinking lung tumors by at least half in 18.7 percent of seriously ill patients who failed to respond to conventional chemotherapy. In 52.9 percent of patients the disease stabilized." A study of OSI-774, a similar drug, showed close to 50% of patients with disease stabilization for at least three months. Iressa is now scheduled to enter stage 3 clinical trials. It has shown success in stabilizing non small lung cancer patients with limited side effects.
1.5 IRESSA AND MESOTHELIOMA CLINICAL TRIALS
The critical question is whether Iressa has shown success in treating patients with mesothelioma. While there are similarities between non-small cell lung cancer and mesothelioma, there are important differences too. Mesothelioma is located in the pleura unlike most non-small cell tumors. Unlike non-small cell lung cancer, mesothelioma's typical progression does not involve metastases to distant organs. Thus, one cannot assume Iressa impressive success with non small cell automoatically translates to success with mesothelioma.
Unfortunately, there have been limited trials with mesothelioma.
2.1 IRESSA AND CHEMOTHERAPY AND RADIATION
2.11 Iressa compliments chemotherapy
The use of different drugs in combination has become standard in treating lung cancer. There is a rapidly developing consensus that not only is Iressa effective, that it compliments and furthers the work of chemotherapy:"A supra-additive growth inhibitory effect was observed with all doses of ZD 1839 and each cytotoxic drug tested in all the cancer lines examined. The cooperative growth inhibitory effect of cytotoxic drugs and ZD 1839 was shown to involve the induction of apotosis (cell death). In fact,treatment with ZD 1839 potentiated cytotoxic drug induced apoptoxis by approximately 2 to 3.5 fold.
The increase in cyto toxicity obtained by blocking EGFR activiation with ZD 1839 appears to be independent of the mechanisms (s) of action of the chemotherapeutic agents. In fact, an enhanced effect was found with structurally and functionally different drugs. Studies have also used ZD 1839 and cytotoxic drugs (paclitaxel, topotecan or raltitexed) in vivo in murine models of human tumors. A cooperative antitumor effect was observed with each combination; there was a signficant suppression of tumor growth and prolonged survival. This effect was most pronounced with the ZD 1839 plus paclitaxel cominaton. " See Ciardiello, EGFR-Targeted Agents Potentiate the Antitumor Activity of Chemotherapy and Radiotherapy,Signal, Volume 2, number 2, (2001) 4.6
2.32 IRESSA AND MESOTHELIOMA CLINICAL TRIALS
As set forth below, there is a large ongoing clinical trial of Iressa for mesothelioma patients. However, we have not located any trials with reported results. Thus, the drug is experimental for mesothelioma, though it has shown effectiveness for nonsmall lung cancer with few side effects.
TREATMENT: Patients will receive ZD 1839 by mouth once a day for as long as benefit is shown. Patients will be evaluated every 2 months for 1 year and then every 6 months for up to 3 years.
This abstract is intended to give a brief overview of this clinical trial. To help determine whether the trial is appropriate for an individual, selected major eligibility criteria are listed above. To obtain more details related to trial eligibility and the treatment plan, please see the Health Professional abstract of this clinical trial. For more information about clinical trials, please visit the NCI cancerTrials Web site at http://cancertrials.nci.nih.gov.
Ramaswamy Govindan, Chair Ph: 314-362-4819
Cancer and Leukemia Group B
RATIONALE: Biological therapies such as ZD 1839 may interfere with the growth of the tumor cells and slow the growth of malignant mesothelioma.
PURPOSE: Phase II trial to study the effectiveness of ZD 1839 in treating patients who have malignant mesothelioma.
Francisco Robert, Ph: 205-934-5077 Veterans Affairs Medical Center - Birmingham Birmingham, Alabama, U.S.A.
Alan T. Lefor, Ph: 310-423-5874 Cedars-Sinai Medical Center Los Angeles, California, U.S.A.
Alan Paul Venook, Ph: 415-353-9888 UCSF Cancer Center and Cancer Research Institute San Francisco, California, U.S.A.
Stephen L. Seagren, Ph: 619-543-5303 University of California San Diego Cancer Center La Jolla, California, U.S.A.
Patricia A. Cornett, Ph: 415-221-4810 ext. 3423 Veterans Affairs Medical Center - San Francisco San Francisco, California, U.S.A.
Irving M. Berkowitz, Ph: 302-623-4001 CCOP - Christiana Care Health Services Wilmington, Delaware, U.S.A.
Edward P. Gelmann, Ph: 202-687-7664 Lombardi Cancer Center Washington, District of Columbia, U.S.A.
Joseph Drabick, Ph: 202-782-6751 Walter Reed Army Medical Center Washington, District of Columbia, U.S.A.
Enrique Davila, Ph: 305-535-3310 CCOP - Mount Sinai Medical Center Miami Beach, Florida, U.S.A.
John W. Kugler, Ph: 309-671-3605 CCOP - Illinois Oncology Research Association Peoria, Illinois, U.S.A.
Gini F. Fleming, Ph: 773-702-4400 University of Chicago Cancer Research Center Chicago, Illinois, U.S.A.
Jeffrey A. Sosman, Ph: 312-996-1588 University of Illinois at Chicago Health Sciences Center Chicago, Illinois, U.S.A.
Thomas E. Lad, Ph: 312-996-5985 Veterans Affairs Medical Center - Chicago (Westside Hospital) Chicago, Illinois, U.S.A.
Rafat H. Ansari, Ph: 219-284-7370 CCOP - Northern Indiana CR Consortium South Bend, Indiana, U.S.A.
Gerald H. Clamon, Ph: 319-356-1932 Holden Comprehensive Cancer Center at The University of Iowa Iowa City, Iowa, U.S.A.
L. Herbert Maurer, Ph: 802-447-1836 Veterans Affairs Medical Center - Togus Togus, Maine, U.S.A.
David A. Van Echo, Ph: 410-328-2565 Marlene & Stewart Greenebaum Cancer Center, University of Maryland Baltimore, Maryland, U.S.A.
George P. Canellos, Ph: 617-632-3470 Dana-Farber Cancer Institute Boston, Massachusetts, U.S.A.
Mary Ellen Taplin, Ph: 508-856-2114 University of Massachusetts Memorial Medical Center Worcester, Massachusetts, U.S.A.
Bruce A. Peterson, Ph: 612-624-5631 University of Minnesota Cancer Center Minneapolis, Minnesota, U.S.A.
Sharon Davis Luikart, Ph: 612-725-2000 ext 4135 Veterans Affairs Medical Center - Minneapolis Minneapolis, Minnesota, U.S.A.
Nancy Bartlett, Ph: 314-362-4843 Barnes-Jewish Hospital Saint Louis, Missouri, U.S.A.
Michael C. Perry, Ph: 573-882-4979 Ellis Fischel Cancer Center - Columbia Columbia, Missouri, U.S.A.
Alan Philip Lyss, Ph: 314-996-5514 Missouri Baptist Cancer Center Saint Louis, Missouri, U.S.A.
Michael C. Perry, Ph: 573-882-4979 Veterans Affairs Medical Center - Columbia (Truman Memorial) Columbia, Missouri, U.S.A.
Ramaswamy Govindan, Ph: 314-747-1849 Washington University Barnard Cancer Center Saint Louis, Missouri, U.S.A.
M. Anne Kessinger, Ph: 402-559-7511 University of Nebraska Medical Center Omaha, Nebraska, U.S.A.
John Allan Ellerton, Ph: 702-384-0013 CCOP - Southern Nevada Cancer Research Foundation Las Vegas, Nevada, U.S.A.
Marc Stuart Ernstoff, Ph: 603-650-5534 Norris Cotton Cancer Center Lebanon, New Hampshire, U.S.A.
Vincent P. Vinciguerra, Ph: 516-562-8954 CCOP - North Shore University Hospital Manhasset, New York, U.S.A.
Jeffrey J. Kirshner, Ph: 315-472-7504 CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C. Syracuse, New York, U.S.A.
George J. Bosl, Ph: 212-639-8473 Memorial Sloan-Kettering Cancer Center New York, New York, U.S.A.
Lewis R. Silverman, Ph: 212-241-5520 Mount Sinai Medical Center, NY New York, New York, U.S.A.
Michael W. Schuster, Ph: 212-746-2119 New York Presbyterian Hospital - Cornell Campus New York, New York, U.S.A.
Daniel R. Budman, Ph: 516-562-8958 North Shore University Hospital Manhasset, New York, U.S.A.
Ellis G. Levine, Ph: 716-845-8547 Roswell Park Cancer Institute Buffalo, New York, U.S.A.
Stephen L. Graziano, Ph: 315-464-8200 State University of New York - Upstate Medical University Syracuse, New York, U.S.A.
Monica B. Spaulding, Ph: 716-862-3191 Veterans Affairs Medical Center - Buffalo Buffalo, New York, U.S.A.
Stephen L. Graziano, Ph: 315-464-8200 Veterans Affairs Medical Center - Syracuse Syracuse, New York, U.S.A.
James N. Atkins, Ph: 919-580-0000 CCOP - Southeast Cancer Control Consortium Winston-Salem, North Carolina, U.S.A.
David Duane Hurd, Ph: 336-716-2088 Comprehensive Cancer Center at Wake Forest University Winston-Salem, North Carolina, U.S.A.
Jeffrey Crawford, Ph: 919-684-5621 Duke Comprehensive Cancer Center Durham, North Carolina, U.S.A.
Thomas C. Shea, Ph: 919-966-7746 Lineberger Comprehensive Cancer Center, UNC Chapel Hill, North Carolina, U.S.A.
Jeffrey Crawford, Ph: 919-684-5621 Veterans Affairs Medical Center - Durham Durham, North Carolina, U.S.A.
Clara D. Bloomfield, Ph: 614-293-7518 Arthur G. James Cancer Hospital - Ohio State University Columbus, Ohio, U.S.A.
Richard K. Shadduck, Ph: 412-578-4355 Western Pennsylvania Hospital Pittsburgh, Pennsylvania, U.S.A.
Louis A. Leone, Ph: 401-444-5391 Rhode Island Hospital Providence, Rhode Island, U.S.A.
Jeffrey Kent Giguere, Ph: 864-987-7000 CCOP - Greenville Greenville, South Carolina, U.S.A.
Mark R. Green, Ph: 843-792-4271 Medical University of South Carolina Charleston, South Carolina, U.S.A.
Harvey B. Niell, Ph: 901-448-5150 University of Tennessee, Memphis Cancer Center Memphis, Tennessee, U.S.A.
Harvey B. Niell, Ph: 901-448-5150 Veterans Affairs Medical Center - Memphis Memphis, Tennessee, U.S.A.
L. Herbert Maurer, Ph: 802-447-1836 CCOP - Southwestern Vermont Regional Cancer Center Bennington, Vermont, U.S.A.
Hyman Bernard Muss, Ph: 802-847-3827 Vermont Cancer Center Burlington, Vermont, U.S.A.
Joseph F. O'Donnell, Ph: 802-295-9363 Veterans Affairs Medical Center - White River Junction White River Junction, Vermont, U.S.A.
John D. Roberts, Ph: 804-628-1940 MBCCOP - Massey Cancer Center Richmond, Virginia, U.S.A.
John D. Roberts, Ph: 804-628-1940 Veterans Affairs Medical Center - Richmond Richmond, Virginia, U.S.A.
2.6 HOW PATIENTS CAN OBTAIN IRESSA
2.61 No FDA Approval as of January 1, 2002
As of this writing, Iressa is not an FDA approved drug for lung cancer, or any other type of tumor.
2.62 Compassionate Use
The availability of non-FDA approved drugs depends in large part upon a manufacturers policies. Expanded use is a program which permits certain patients to obtain access to an experimental drug before FDA approval and outside the context of a clinical trials. Clinical trials require the patient to be placed in one of two of three treatment groups. Some manufacturers have been reluctant to provide extensive access to new drugs for fear that patients would y use the new trial rather than enter into the clinical trial. Without successful clinical trials, the drugs cannot be approved.
2.63 Astra-Zeneca Policies
Astra-Zenecas appears to be providing liberal use of Iressa. In particular, it appears stage 4 patients may obtain the drug through a physician authorized by Astra-Zeneca to prescribe it. However, the precise policies are unclear, unpublished, and changeable. It appears stage 3 trials are under way, and policies may change.
See Ciardiello, EGFR-Targeted Agents Potentiate the Antitumor Activity of Chemotherapy and Radiotherapy,Signal, Volume 2, number 2, (2001) 4.
2.64 Combining Iressa with Similar Drugs
There have been limited side effects with Iressa. The maximum effective dose appears to be less than the maximum tolerable dose. That is, additional amounts of Iressa could apparently be tolerated by the body, but since no incremental effectiveness is shown, the added amounts would not be given.
Thus, there is apparently room or tolerance to combine Iressa with similar drugs like OSI-774 or even ImClones IC 225. Perhaps the main barrier is not effectiveness but market strategy. Each manufacturer may be eager to tout its own product but as with chemotherapy, less eager to discuss combinations. However, impartial researchers should seek the best combinations. Assuming Iressa is FDA approved, the next step is to compare its effectiveness in various combinations.
2.65 Future Clinical Research
Thus we can foresee a group like ECOG (Easters Cooperative Oncology Group) conducting a phase 3 clinical trial dividing patients with advanced cancer into the following groups:
1) Iressa and Carboplatin
2) Iressa, OSI-774, and Carboplatin,
3) Iressa, OSI-774, ICC 225, and Carboplatin.
A multi-drug combination as in 3 might seem imposing, but could pose the best opportunity for cure, given that each of these gene therapies have been well-tolerated. Indeed, a similar clinical trial is being planned,
2.7 OTHER EPIDERMAL GROWTH FACTOR THERAPIES
OSI-774 is a less publicized epidermal growth factor inhibitor which is also showing promising results. In a phase 1 clinical trial, "OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease."Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase.
A presentation at a 2001 cancer conference said, "OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, was shown to have impressive single agent activity in the second-line treatment of lung cancer" though it did not delineate specific results in the abstract. Lung Cancer, Oncologist 2001; 6 (5): 407-14
2.82 Side Effects
As with Iressa, side effects have been limited. One journal did report the incidence of severe diarrhea and/or cutaneous toxicity was unacceptably high at OSI-774 doses exceeding 150 mg/d." Hidalso, Phase I and pharmacologic study of OSI-774, An epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies, J Clin Oncol 2001 Jul 1;19(13):3267-79.
Howard Gutman is a New Jersey attorney based in Parsippany, New Jersey who has handled numerous legal claims involving pulmonary tumors. A member of the board of directors of a leading cancer support group, he is the author of the upcoming book, A Complete Guide to Lung Cancer. He has appeared on Good Day New York, spoken at the National Press Club and been interviewed by NBC Nightly News.
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