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 May;21(5):1023-9.
"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 Jul;81(7):733-44
"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 growth factor."
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 asbestos fibers.

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.

ELIGIBILITY:

At least 19 years old
Measurable disease
No brain metastases
No previous chemotherapy for malignant mesothelioma
At least 4 weeks since radiation therapy
At least 2 weeks since surgery

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.

PROTOCOL IDS

CLB-30101

Ramaswamy Govindan, Chair Ph: 314-362-4819
Cancer and Leukemia Group B

PATIENT ABSTRACT

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.

Locations

STUDY CONTACTS

U.S.A.

Alabama

Francisco Robert, Ph: 205-934-5077
Veterans Affairs Medical Center - Birmingham
Birmingham, Alabama, U.S.A.

California

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.

Delaware

Irving M. Berkowitz, Ph: 302-623-4001
CCOP - Christiana Care Health Services
Wilmington, Delaware, U.S.A.

District of Columbia

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.

Florida

Enrique Davila, Ph: 305-535-3310
CCOP - Mount Sinai Medical Center
Miami Beach, Florida, U.S.A.

Illinois

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.

Indiana

Rafat H. Ansari, Ph: 219-284-7370
CCOP - Northern Indiana CR Consortium
South Bend, Indiana, U.S.A.

Iowa

Gerald H. Clamon, Ph: 319-356-1932
Holden Comprehensive Cancer Center at The University of Iowa
Iowa City, Iowa, U.S.A.

Maine

L. Herbert Maurer, Ph: 802-447-1836
Veterans Affairs Medical Center - Togus
Togus, Maine, U.S.A.

Maryland

David A. Van Echo, Ph: 410-328-2565
Marlene & Stewart Greenebaum Cancer Center, University of Maryland
Baltimore, Maryland, U.S.A.

Massachusetts

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.

Minnesota

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.

Missouri

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.

Nebraska

M. Anne Kessinger, Ph: 402-559-7511
University of Nebraska Medical Center
Omaha, Nebraska, U.S.A.

Nevada

John Allan Ellerton, Ph: 702-384-0013
CCOP - Southern Nevada Cancer Research Foundation
Las Vegas, Nevada, U.S.A.

New Hampshire

Marc Stuart Ernstoff, Ph: 603-650-5534
Norris Cotton Cancer Center
Lebanon, New Hampshire, U.S.A.

New York

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.

North Carolina

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.

Ohio

Clara D. Bloomfield, Ph: 614-293-7518
Arthur G. James Cancer Hospital - Ohio State University
Columbus, Ohio, U.S.A.

Pennsylvania

Richard K. Shadduck, Ph: 412-578-4355
Western Pennsylvania Hospital
Pittsburgh, Pennsylvania, U.S.A.

Rhode Island

Louis A. Leone, Ph: 401-444-5391
Rhode Island Hospital
Providence, Rhode Island, U.S.A.

South Carolina

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.

Tennessee

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.

Vermont

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.

Virginia

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 manufacturer’s 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-Zeneca’s 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 ImClone’s 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

2.81 OSI-774

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.

Profile

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.

Contact Information

Telephone: Howard A. Gutman, 973-257-9400; 973-257-9128
Postal address: 230 Route 206, Flanders, New Jersey 07836
Email: Howian@aol.com

Mesothelioma and Asbestos Links Iressa Links

Home Page www.egfr.info.com