REVIEW OF ANTI-ANGIOGENESIS DRUGS FOR LUNG CANCER

It is easier to discuss the uncertainties in anti-angiogenetic research than to suggest a particular course. With over 100 anti-angiogenic clinical trials and no drug yet approved for treatment of lung cancer, the area is uncertain. What is written today could be inaccurate tomorrow as new clinical findings are unveiled. The problem is complicated by the tendency of some companies to exaggerate the results of trials in the interest of promoting their stock. With these caveats, here is a summary.

1.0 WHAT IS ANGIOGENESIS

1.01 Theory

Angiogenesis is the method by which tumors connect to blood vessels to create sources of nutrients and oxygen, resulting in the tumor’s spread and metastasis to other organs. Without angiogenesis, the tumor cannot spread and may die. Solid tumors cannot grow beyond the size of a pinhead (1 to 2 cubic millimeters) without inducing the formation of new blood vessels to supply the nutritional needs of the tumor. If growth factors such as TAF (Tumor Angiogenesis Factor) prompt connection of the tumor with blood vessels, then inhibition of these factors may reduce the tumor’s spread.

1.02 Side Effects

One author suggests, "Most angiogensis inhibitors appear to have less toxicity and no drug resistance, making for an advantageous contrast to conventional cytotoxic drugs.... With chemotherapy showing some but limited utility with advanced cancer, attention has turned to these anti-angiogenic drugs.

"Several differences between standard chemotherapy and anti_angiogenesis therapy result from the fact that angiogenesis inhibitors target dividing endothelial cells rather than tumor

cells. Anti_angiogenic drugs are not likely to cause bone marrow suppression, gastrointestinal symptoms, or hair loss,  symptoms characteristic of standard chemotherapy treatments. Also, since anti_angiogenic drugs may not necessarily kill tumors, but rather hold them in check indefinitely, the endpoint of early clinical trials may be different than for standard therapies. Rather than looking only for tumor response, it may be appropriate to evaluate increases in survival and/or time to disease progression." NationalCancer Institute's website:http://cancertrials.nci.nih.gov."

1.1 GENERAL STATUS OF ANTI-ANGIOGENESIS

1.11. No FDA Approvals to Date

No anti-angiogenesis drugs have been proven to be effective to date with humans (March, 2001). More specifically, none have been approved for use with nonsmall-cell lung cancer. A number of clinical trials are pending testing these drugs on patients with advanced lung cancer (Stage 3B or 4).

1.12 Success in the Laboratory Other Areas.

In a laboratory setting, various anti-angiogenesis drugs have been shown to reduce tumors.

Using in vivo (cellular systems) inhibition of VEGF (vascular endothelial growth factor) has successfully controlled tumor growth, dissemination, and distant metastasis by a variety of VEGF agents such as neutralizing anti-VEGF antibodies, anti-sense VEGF, cDNA, and soluble VEGF receptors. Kim first demonstrated the effectiveness of a monoclonal antibody against tumor cells having VEGF expression in 1993 Current Concepts of Angiogenesis Related to Primary Lung Cancer, in Pass Lung Cancer (2000).

1.131 Success on Other Organs

There are some other forms of cancer where anti-angiogenic drugs have shown success in humans:

"Dr. Judah Folkman, from Children's Hospital, Boston, Massachusetts, reviewed his center's experience treating childhood hemangiomas with interferon-alpha 2a (IFN-alpha). Dr. Folkman noted that this experience serves as a paradigmatic model for trials of angiogenesis inhibitors. Believing that long-term, regular exposure to angiogenesis inhibitors is likely to be critical for treatment success, IFN-alpha has been administered at a dose of 3 million units/m2 given subcutaneously every day. Since the late 1980s, Dr. Folkman and colleagues have treated 74 patients with life-threatening hemangiomas with IFN-alpha. Overall, the treatment failure rate has been only 15%; in the other patients, the hemangiomas stabilized or regressed. In general, IFN-alpha therapy has been well tolerated. Young patients (< 1 year) have developed lower-extremity stiffness and neurologic difficulties that have led to developmental delay, including delayed time to walking." Burstein, Molecular Targets for Novel Cancer Treatments: Tumor Vaccines and Angiogenesis, American Society of Clinical Oncology 36th Annual Meeting

1.2 POTENTIAL OBSTACLES

1.21 Need for Long-Term Treatment

As the above indicated, Folkman achieved his best results over a long-period. For some of the patients, that may not be possible, and for others, we have to hope that sufficient time is given to evaluate the drug. A three month clinical trial may be inadequate to accurately evaluate such a drug.

1.22 Identifying the Predominant Growth Factor

Success in experimental and animal models has not been readily translated into success in clinical trials. The growth of lung cancer appear to depend upon a variety of different growth factors. If the growth of the tumor is not, for example, entirely simply dependent on VEGF (vascular endothelial growth factor) anti-angiogenic therapy directed to that growth factor alone may not be effective. Myoung, Evaluation of the Anti-tumor and Anti-angiogenic effect of Paclitaxel and Thalidomide on the Xenotransplanted Oral Squamous cell carcinoma. Cancer Lett 2001 Feb 26;163(2):191-200

Thus, if there are a number of different growth factors with different influences on different tumors, then we must either isolate the predominant growth factor very specifically, for example, squamous cell lung cancer and epidermal growth factor, or more likely, use a variety of anti-angiogenesic drugs to combat various methods of tumor growth.

1.24 The Difficulty of Delivering the Drug to the Entire Tumor

In experiments with mice, it was easy for the experimentor to administer sufficient doses of a drug to encompass the entire tumor. With humans, there has been some difficulty delivering the drug to the entire relevant area. "In all of these studies, it has been difficult to deliver recombinant virus into solid tumors so as to transduce a significant fraction of the tumor cells, and the effect is limited to the injected nodule, which be of limited real clinical benefit." Lee, Gene Therapy, excerpted in Pass, Lung Cancer (Lippincott 2000). The researcher is discussing gene therapy, but the problem of delivering the drug to the physical area of the tumor, to ensure complete inhibition of growth factors remains a perplexing one. It may be that researchers will look for the more modest goal of improving chemotherapy, than creating a new form of cure.

1.4 SOME SELECTED ANTI-ANGIOGENESIS DRUGS

1.41 Iressa

1.411 Mechanisms of Action

Iressa or ZD 1839 is a promising new drug. "Iressa blocks a pathway implicated in a variety of solid tumors. The pathway is triggered by an epidermal growth factor that binds to an epidermal growth factor receptor (EGFr) that sends signals within the cell via tyrosine kinase. Blocking the tyrosine kinase switches off the signals from the EGFr, potentially stopping tumor growth." See Iressa Shows Promising AntiTumor Activity and is Well Tolerated with Minimal Side Effects: Oncology News, vo. 9, no. 7, Supp 3 (July 2000).

1.412 Media Report of Clinical Studies and Research

Iressa or ZD 1839, is a drug which has shown some beneficial effects in initial clinical trials regarding lung cancer. See Iressa Shows Promising AntiTumor Activity and is Well Tolerated with Minimal Side Effects: Oncology News, vo. 9, no. 7, Supp 3 (July 2000). The article reported a 25% response rate in patients with advanced cancer. For head and neck tumors, the response rate was 54%. Dr. David Ferry stated, "Iressa is a medication that is easy for patients to take. It is well tolerated with minimal side effects. To our surprise, it is active as a single agent, at least in non-small-cell lung cancer." Id at 2. See also Finkelstein, Experimental Drug Shows Promise Against Solid Tumors, oncology.com. The article indicates it is being used at New York’s prestigious Sloan-Kettering Cancer Center as well as other facilities:

"Dr Mark Kris, chief of the Thoracic Oncology Service at the Memorial Sloan-Kettering Cancer Centre in New York, who conducted the analysis of the phase I trial results said today: "We were surprised and encouraged to see clinical responses at this early stage of development as these early clinical evaluations of ZD1839 were essentially designed just to assess the safety of the compound in patients and to find the right dose to take forward into larger clinical trials. However, while they are encouraging, these results are only a starting point for further extensive studies which are now underway."

Another report was not as enthusiastic. The article first explains how ZD 1839 works:

"Dr. Lesley Seymour gave a presentation on behalf of the National Cancer Institute of Canada, on the preliminary results of a phase 1 and biological study of ZD-1839. This is a novel specific inhibitor of the epidermal growth factor receptor (EGFR), currently in clinical development. The agent binds to the adenosine triphosphate (ATP)-binding pocket of the EGFR, inhibiting receptor phosphorylation and activation, and, thus, blocking the EGFR-dependent signaling pathways. The agent demonstrated substantial antitumor activity in preclinical models and showed clear mechanistic-based tumor-growth inhibition properties, in that concentrations at which the EGFR inhibition was achieved were associated with optimal tumor-growth inhibitory actions....

However, the researchers were not able to document elevated levels of the epidermal growth factor:

Patients treated with ZD-1839 had a tumor biopsy collected at baseline and after the completion of the first cycle of treatment. These tissue specimens were used for biological studies, including studies of EGFR expression, EGFR activation, EGFR signaling activation, and cell proliferation and apoptosis. Unfortunately, the results of the biological studies presented were disappointing. Although all of these patients had EGFR-positive tumors, only 1 case had actually phosphorylated (activated) EGFR. This is a very unusual finding, and may reflect technical problems with the laboratory system used to determine EGFR activation, rather than having validity as a clinical finding. In addition, some data were presented regarding cell proliferation and apoptosis although, again, the low number of cases limits the conclusions that can be drawn Sessa, 25th Congress of the European Society for Medical Oncology , Antitumor Activity and Toxicity of New Compounds, Medscape.com This Canadian report does not report the 25% rate of success, and indicates the study was discontinued, though it appears phase 2 and 3 trials are scheduled.

 

1.413 Published Medical Research on Iressa.

Medical journals tend to be more reliable than the news media. With Iressa, there is a published study discussing the results of the recent phase I trials confirming thatIressa has had only limited side effects and has shown some ability to reduce advanced metastatic cancers. This wasa phase I trial at which researchers were attempting to define the appropriate dose, one at which the drug would have a maximum effect with tolerable side effects. With these limitations, favorable results were reported :

"ZD1839 (Iressa) is an orally active, selective EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) which blocks signal transduction pathways implicated in cancer growth and survival. The objective of this trial is to investigate the tolerability, pharmacokinetics and efficacy of intermittent daily oral dosing of ZD1839 in Japanese patients (pts) with solid tumors known to commonly express or overexpress EGFR. To date, 25 pts with NSCLC (20), CRC (4) and H & N (1) tumors have been recruited. Pts received a single oral dose of ZD1839 and were observed for 10 to 14 days. Then they received the same dose as the single dose repeatedly for the following 14 days (once daily) followed by 14 days observation (50 mg [n=5], 100 mg [n=4], 225 mg [n=6], 400 mg [n=4] and 525 mg [n=6]). No dose-limiting toxicity was observed at doses up to 525 mg. One pt at 225 mg and one pt at 525 mg had grade 3 elevation of GOT and GPT. The most frequent adverse drug reactions were skin symptoms (rash, ache, sebhorrea, etc), digestive symptoms (nausea, anorexia, vomiting, etc) and increases of GOT and GPT. To date, 3 pts with NSCLC have shown partial responses (at 225mg, 400 mg and 525 mg, confirmed). In conclusion, interim results indicate that once-daily oral ZD1839 is well tolerated and shows evidence of clinical activity in Japanese pts. Updated results will be presented at the Conference. " Uejima, A phase I intermittent dose-escalation trial of ZD1839 (Iressa™™) in Japanese patients with solid tumors. Annals of Oncology, Vol 11, Suppl.4 October 2000, page 110

1.414 Limitations

The 25% partial response rate in one report while impressive is about the same as various forms of chemotherapy such as carboplatin combinations. Phase 3 trials will have to determine whether the initial promising results can be replicated and the drug’s place in lung cancer treatment. Will the drug be used only where prior chemotherapy has failed, included with chemotherapy, or used in some other fashion. Recent clinical trials are using the drug in conjunction with established form of chemotherapy. If when coupled with chemotherapy, the drug further reduces tumors and thereby increases survival time, we can expect FDA approval. With some demonstrable success with lung cancer, this drug will be carefully evaluated by patients with advanced disease and their physicians.

1.415 Pending Clinical Trials

The website Cybermed.com has a description of the Sloan Kettering clinical trial of ZD 1839 which it titles. Study of ZD 1839, an Epidermal Growth Factor Receptor Inhibitor, and Carboplatin/ Taxol Chemotherapy in the Treatment of Advanced or Metastatic Non-Small Cell Lung Cancer. All patients receive carboplatin and taxol, with different groups receiving varying amounts of ZD 1839 in addition. The study is limited to those with advanced cancer who have not received prior chemotherapy or biological therapy, there may be circumstances where the drug can be made available to those ineligible for the trial.

1.42 THALIDOMIDE

1.421 Mechanisms of Action

Thalidomide is a drug originally used in Europe which was found to cause fetal abnormalities. "Limb defects seen with the drug were secondary to an inhibition of blood vessel growth in the developing fetal limb bud." Pass, Lung Cancer 898 (2000). The drug demonstrates the close relationship between normal gene multiplication, divisions, and blood vessel growth and those associated with cancer and metastasis.

1.423 Thalidomide and Radiation

One experiment found that while thalidomide did not reduce tumor growth, it made the tumors more susceptible to radiation.

We have investigated the effect of thalidomide on growth, radiosensitivity and metastasis in murine SCCVII and Lewis Lung tumors. We found that daily thalidomide administration (0.77 mmol/kg/day, i.p.) does not alter primary tumor growth of SCCVII or Lewis Lung tumors. However, thalidomide administration does reduce radiosensitivity of the Lewis Lung tumor, and increases its sensitivity to combined treatment with radiation and the bioreductive cytotoxin tirapazamine. These findings suggest that thalidomide is elevating tumor hypoxia in the Lewis Lung tumor, presumably via an anti-angiogenic mechanism. We also found that thalidomide administration reduces the incidence of lung metastases from primary Lewis Lung tumors. Thalidomide may therefore have utility in the management of solid tumors, especially when combined with drugs that are selectively toxic to cells at reduced oxygen tension (e.g. bioreductive cytotoxins). Micninton, The Effect of Thalidomide on experimental tumors and metastases Anticancer Drugs 1996 May;7(3):339-43.

It does not appear that the idea of using thalidomide to improve radiation has been followed up. It may be that the use is too limited, and more attention has focused on thalidomide and other diseases where its effectiveness has been clearer

1.424 Human Trials OF Thalidomide

Moderate and conflicting results have been shown with thalidomide and various cancers. A study of thalidomide with gliomas, a type of cancer, found:.

"A total of 39 patients were accrued.... Thalidomide was well tolerated, with constipation and sedation being the major toxicities.... There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas." Fine, Phase II Trial of the Antiangiogenic Agent Thalidomide in Patients with Recurrent High-Grade Gliomas J. Clin Oncol. 2000;18(4):708-15

A result study with metastatic breast cancer found no response with Thalidomide.("Conclusion: Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer,"

Phase II evaluation of Thalidomide in Patients with Metastatic Breast Cancer, J Clin Oncol 2000 Jul;18(14):2710-7 . Substantial responses with lung cancer are not shown in either study, and with at least metastatic lung cancer, the drug is highly experimental. For an overview, see Medscape.com,Abstracts, Thalidomide Clinical Trials (2000)

1.43 Angiostatin

      1.431 Dr. Folkman, History and Animal Studies

 

Dr. Judah Folkman pioneered anti-angiogenetic research and Angiostatin was one of his findings.

While its findings have been promising at times, it has been steeped in controversy. In a laboratory, Folkman was able to show significant tumor reductions on mice with administration of Angiostatin. Entremed, the commercial developer of Angiostatin, saw its stock rose meteorically with initial suggestions of a cancer cure. Later, however, scientists found that they were not able to duplicate his results in their laboratories. See King, Novel Cancer Approach from Noted Scientist Hits Stumbling Block, with the subheading, "So Far, Others Can’t Match Folkman’s Feat: Ending a Tumor’s Blood Supply." Wall St. Journal, November 12, 1998. Later, it appears that the National Cancer Institute was able to replicate the results in Folkman’s laboratory. See Cooke, Dr. Folkman’s War, Angiogenesis and the Struggle to Defeat Cancer 298 (2000).

A recent article again showed Angiostatin’s promise in a laboratory setting.

"The possibility to inhibit tumor growth by interfering with the formation of new vessels, which most neoplasias depend on, has recently raised considerable interest. An angiogenic switch, in which proliferating cells acquire the ability to direct new vessel formation, is thought to be an early step in the natural history of solid tumors. Using a transgenic model of breast cancer, which shows many similarities to its human counterpart, including ability to metastasize, we targeted angiostatin production to an early stage of tumor formation. Liposome-delivered angiostatin considerably delayed primary tumor growth and, more importantly, inhibited the appearance of lung metastasises. These findings can be relevant to the design of therapeutic intervention in humans." Sacco, "Liposome-delivered angiostatin strongly inhibits tumor growth and metastatization in a transgenic model of spontaneous breast cancer."Cancer Res, 2000 00, 60: 10, 2660-5

Similar findings were made in another study:

"Ovarian cancer growth is angiogenesis-dependent, and an increased production of angiogenic growth factors such as vascular endothelial growth factor is prognostically significant even during early stages of the disease. Therefore, we investigated whether antiangiogenic treatment can be used to inhibit the growth of ovarian cancer in an experimental model system.... Purified angiostatin and endostatin were (used) to treat established ovarian cancers in thymic mice. These studies showed that both angiostatin and endostatin inhibited tumor growth. However, angiostatin treatment was more effective in inhibiting ovarian cancer growth when compared with endostatin in parallel experiments. Residual tumors obtained from angiostatin- and endostatin-treated animals showed decreased number of blood vessels and, as a consequence, increased apoptosis of tumor cells. Subsequently, the efficacy of a combined treatment with angiostatin and endostatin was investigated. In the presence of both angiostatic proteins, endothelial cell proliferation was synergistically inhibited. Similarly, a combination regimen using equal amounts of angiostatin and endostatin showed more than additive effect in tumor growth inhibition when compared with treatment with individual angiostatic protein. These studies demonstrate synergism between two angiostatic molecules and that antiangiogenic therapy can be used to inhibit ovarian cancer growth."Yokoyama Synergy between Angiostatin and Endostatin: Inhibition of Ovarian Cancer Growth." Cancer Res, 2000 00, 60: 8, 2190

See also, Feldman, Antiangiogenic gene therapy of cancer utilizing a recombinant adenovirus to elevate systemic endostatin levels in mice, Cancer Res, 2000 00, 60: 6, 1503 (reduction in volume of previously resistant adenocarcinoma by 40%

The article suggests that some of the difficulties scientists had with duplicating Folkman’s findings have been overcome, and that a combination of angiostatin and endostatin merits review in clinical trials. Another article found that when investigating liver cancer, continuous administration of the drug improved results. Drixler, "Continuous administration of angiostatin inhibits accelerated growth of colorectal liver metastasises after partial hepatectomy."Cancer Res, 2000 00, 60: 6, 1761-5. A recent study found that at least certain types of cancers seems to prompt the natural production of angiostatin by the body. Cao, Elevated levels of urine angiostatin and plasminogen/plasmin in cancer patients, Int J Mol Med, 2000 05, 5: 5, 547-51

1.432 Combining Anti-Angiogenesis Inhibitors in a Laboratory or Animal Model

The Yokoyama article persuasively argues that a combination of angiostatin and endostatin would function better than either alone. Indeed for chemotherapy, using a number of different drugs with different mechanisms of action has become standard practice. A recent book says this also, " In in vivo experimental model systems, the treatment by a combination of anti-angiogiogencic drugs have been found to be more effective compared to that by only a single agent. In addition a combination therapy using both antiangiogeneic agents and cytotoxic anti-cancer drugs has also been show to have a greater effect. Ohta, Current Concepts of Angiogenesis Related to Primary Lung Cancer, in Pass, Lung Cancer 206 (Lippincott 2000)

1.433 Human Studies of Angiostatin

However, translating laboratory success to a drug which frustrates metastasis in humans with advanced cancer has proven difficulty, and Angiostatin has not shown the promise in clinical trials that many had predicted or at least hoped for. In February, 1999, Bristol-Meyers which had co-sponsored angiostatin research decided to abandon it. See Cooke, Dr. Folkman’s War, Angiogenesis and the Struggle to Defeat Cancer 304 (2000).

"The feasibility of serial tumor sampling was demonstrated by Dr. Lesley Seymour and colleagues[6] in the Canadian multicenter phase 1 study of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD 1839. ZD 1839 blocks EGFR activation, which, in turn, affects expression and tumor growth. The agent was given daily for 28 days at increasing doses from 150 mg/day to 800 mg/day. Tumor sampling, consisting of punch biopsy, core biopsy, or fine needle aspiration, was performed before starting treatment and at the end of cycle 1 on day 29. The samples were evaluated for EGFR expression, mutations, and phosphorylation, as well as Ki67 and apoptosis, before and after treatment.

Of the 28 patients initially sampled, only 12 were biopsied on day 29, primarily because of early tumor progression coupled with discontinuation of treatment before study end. The limited number of observations, therefore, did not allow the researchers to draw conclusions regarding a possible correlation between the agent's biologic effects and its antitumor activity. Pharmacodynamic end points have been included in the ongoing phase 2-phase 3 studies; it is likely that their results will be of prime importance in the dosing and scheduling of treatments."

 

1.5 MATRIX METALLOPROTEINASIS

1.50 Overview

Most bodily structures have a covering which maintains its structural integrity. However, "a cascade of degradative enzymes clears a path at the advancing edges of invasive tumors into and through which the tumor cells move." Vile, Cancer Metastasis: From Mechanisms to Treatment (Wily & Sons 1995). This process is call matrix metalloproteasasis or MMP. "Liotta et al.

proposed a `three step theory' on basement membrane infiltration in the complex process of cancer metastasis: cancer cells adhere to the basement membrane, release enzymes which degrade its components, and move through the thus generated cavities in the basement membrane." Fujise, Prognostic impact of Cathepsin B and matrix metalloproteinase-9 in pulmonary adenocarcinomas by immunohistochemical study, Lung Cancer, Vol. 27 (1) (2000) pp. 19-26

Drugs have been developed to frustrate this process called MMPI, but have not to date been proven effective in clinical trials. This note summarizes the status of two well-know MMP drugs, Prinomastat and Marimastat:

"Anti-angiogenesis remains an active area of cancer research, despite the fact that no angiogenesis inhibitor has entered the market. Recent setbacks for two agents British Biotech's Marimastat and recently Pfizer's Prinomastat, have not dampened enthusiasm for anti-angiogenic drugs. In fact, results from the American Society of Clinical Oncology (ASCO) and the American Association for Cancer Research (AACR) both suggest that anti-angiogenic agents still hold much promise for the treatment of cancer." www.biospace.com

1.511 Prinomastat Laboratory Research

Initial laboratory results were reported as promising:

"Agouron Pharmaceuticals, Inc., today announced that it has initiated a second Phase III clinical trial of the matrix metalloprotease (MMP) inhibitor prinomastat (formerly AG3340) in combination with chemotherapy in patients with advanced non-small cell lung cancer. In preclinical models, prinomastat has been shown to potently inhibit angiogenesis (the formation of new blood vessels which feed growing tumors), tumor invasion, and metastasis. This trial is designed to evaluate the safety and efficacy of prinomastat as part of first-line therapy in combination with chemotherapy, an effort led by ongoing Phase III clinical trials."

Press Release, Agueoron Announces Confirmatory Trial Of Oral Anti-Angiogenesis Drug Prinomastat For Treatment Of Lung Cancer, August 19. 1999

1.512 Prinomastat Human Trials

However, clinical trials have not confirmed initial findings, confirming the difficulty of translating a drug effective on tissue in a laboratory, into an effective treatment for humans. The difficulty of delivering the drug to the entire tumor, confirming that a particular protein or growth factor is responsible for angiogenesis as well as any number of other factors have made the task difficult.

" Pfizer announced today that preliminary results of phase III clinical trials of prinomastat, a matrix metalloprotease inhibitor (MMPI), in advanced hormone refractory prostate cancer and advanced (Stage IV) non-small cell lung cancer did not meet primary efficacy objectives. Neither detrimental nor convincing beneficial effect of the combination of prinomastat with standard chemotherapy was observed. Consequently, Pfizer is halting these two phase III trials." Www.Prnewswire.com, August 4, 2000, Pfizer Discontinues Phase III Trials of Prinomastat in Advanced Cancers but Continues Multiple Phase II Trials

The Angiogenesis Foundation provides this sensible analysis:

"The pharmaceutical company Pfizer announced today that it halted its Phase III clinical trials of the antiangiogenic drug Prinomastat (AG3340) for both advanced non-small cell lung cancer and prostate cancer, due to the drug's lack of effectiveness in patients with late-stage disease. According to Pfizer, patient safety was not a factor in this decision. Several earlier stage clinical trials of Prinomastat are to continue, for glioblastoma, cancer of the esophagus, melanoma, and breast cancer. Prinomastat is an oral antiangiogenic drug that belongs to a new class of therapeutics known as matrix metalloproteinase inhibitors (MMPI). MMPIs interfere with enzymes that are involved in both angiogenesis and tumor invasion.

The decision to halt Prinomastat comes as the worldwide effort to develop safe and effective antiangiogenic drugs for cancer accelerates rapidly. There are presently 51 drug, including Prinomastat, in oncology clinical trials in human cancer patients. Prinomastat was one of 15 antiangiogenic agents in Phase III clinical trials. Presently, 12 antiangiogenic agents remain as strong contenders in the race.

The division of Pfizer responsible for antiangiogenic drug development, Agouron Pharmaceuticals, will continue to develop other experimental antiangiogenic agents for cancer.

Prinomastat is the third matrix metalloproteinase inhibitor (MMPI) to be halted in the final stages of development. Last year, two other drugs, Bay 12,9566, sponsored by Bayer Corporation, and MMI-270, sponsored by Novartis, were also stopped. All three drugs were being developed for non-small cell lung cancer, as well as several other tumor types. Only Prinomastat was halted solely for lack of effectiveness. Bay 12,9566 was stopped due to more rapid tumor growth in patients treated with the drug. MMI-270 was halted because of poorly tolerated joint and muscular pains.

According to Angiogenesis Foundation's experts, there are at least two possible explanations for Prinomastat's poor performance in its Phase III trials:

* Suboptimal clinical trial design - the Prinomastat Phase III trials enrolled patients with very advanced, late-stage disease. Inhibiting matrix metalloproteinases as a strategy to starve tumors may be more effective in earlier stages of disease, when tumors are smaller and may be more sensitive to these agents. Recent research from Dr. Roberto Nicosia's laboratory in Seattle, Washington has also shown that MMP inhibition may lead to slowing of angiogenesis early in the process of blood vessel growth, while in later stages of angiogenesis, MMP inhibition may lead to stabilization of the blood vessels, making them more permanent. The Angiogenesis Foundation is currently meeting with numerous biopharmaceutical companies to discuss techniques that may help fine tune clinical trial design in the angiogenesis field.

* Biological reasons - Prinomastat was designed to be highly selective for several specific matrix metalloproteinase enzymes (2,9, 21). There are at least 20 such enzymes in total, and Prinomastat's selectivity may not be sufficient enough to cause significant inhibition of cancer growth. Furthermore, suppressing several enzymes may also lead to increased production by cancer cells of the remaining enzymes, leading to continued tumor growth.

The precise reasons for Prinomastat's failure will remain unknown until further research on the drug is conducted" August 7, 2000, Phase III Clinical Trial of Prinomastat Halted, www.angio.org.

Let us look more closely at some of these factors. It is unlikely that Pfizer include particularly ill patients in its study. However, Dr. Folkman did note that it may take some time for anti-angiogenetic drugs to work. The most likely explanation is that there are various enzymes and that the drugs did not sufficient target those predominantly involved in this process. While more MMP research is possible, there have been a few success in other areas, and it is more likely that researchers will try to build upon those successes than try to reinvigorate a drug type which has failed in several trials.

1.6 GENE THERAPY

1.61 Role of the P-53 Gene

P-53 is a tumor suppressor gene. Recall that cancer results from activation of growth proto-oncogenes and inhibition of tumor-suppressor genes such as P-53. Its role is critical:

"p53 protein...mediates several cellular functions: regulation of the cell division cycle, DNA repair, and programmed cell death.DNA repair, and programmed cell death. In response to various forms of genomic DNA damage... the p53 protein can arrest the cell cycle at the G1 to S transition point, thus affording time for DNA repair andpreventing duplication of a mutant cell, or alternatively, failing DNA repair, p53 protein can implement programmed cell death (apoptosis). Accordingly, p53 has been dubbed the "guardian of the genome." Etiology of Cancer:Carcinogeneis  http:/edcenter.med.cornell.edu.

 

1.62 Wild and Mutant type P-53 Genes

P-53 is a protein of 53 kilodaltons. It is located on chromosome 17 (p13). There are two types of P-53. First, there is normal P-53 also called wild-type P-53. This is P-53 in its normal condition, serving various tumor suppression functions outlined above. Mutant P-53 means the gene has been damaged. Not only will the gene not perform its tumor suppressor function, evidence indicates it plays a role in prompting duplication of cells:" Mutant p53 loses its original function but may acquire a new potentially oncogenic activity. Conversion of p53 protein from a normal to a mutant phenotype alters its histochemical feautres; the half-life of the protein is proloned from 6-20 minutes to several  hours. This increases the amount of p53 protein in affected cells,... Detection of excessive amounts of p53 protein is useful as a marker of mutation because the amount of wild-type p53 protein is too low to be detected in nonmutant cells." Gemba, Immunohitochemical Detection of Mutant P53 protein in Small Cell Lung Cancer: Relationship to Treatment Outcome, Lung Cancer, vol 29 (1) (2000) pp. 23-31.

1.63 With What Cancers is P-53 Damage Associated

P-53 damage occurs in approximately 50% of the following cancers: breast colon, stomach, bladder, and non-small cell lung cancer. "In non-small cell lung cancer (NSCLC), most series report that 50% to 60% of tumors have identifiable mutations." Szak, P53 in Pass, Lung Cancer: Principles and Practice (2000).

1.64 P53 and Small Cell Lung Cancer

A 1999 study found that 52% of the patient had traces of P53 in bronchial specimens. Gemba, Immunohitochemical Detection of Mutant P53 protein in Small Cell Lung Cancer: Relationship to Treatment Outcome, Lung Cancer, vol 29 (1) (2000) pp. 23-31. P53 presence was unfortunately a negative factor for these patients. "The overall response rate of patients

in the p53 -positive group was significantly lower than that in the P53 negative group." Gemba, id. However, P53 does not seem to be correlated with other factors such as stage of disease. In another study, bronchial specimens from lung cancer patients " were used for detection of p53 gene mutation.... 15 of 25 (60%) specimens were found to be positive. In 10 small cell lung cancer specimens, 7 were positive; in 15 non-small lung cancer specimens, 8 were positive. Clinical analysis showed no correlation between positivity and the patients' clinical data such as age, sex, smoking habit, stage of tumor at the time of diagnosis."

13.46 Cell Experimentation

If this damage to P-53 could be repaired, then tumor spread could be limited and perhaps P-53 could again perform its function of preventing cell duplication. This type of treatment has worked in the laboratory dealing with cancer cells:

"Reintroducing a wild-type p53 gene into lung cancer cells, including bronchioalveolar lung cancer (BAC), dramatically inhibits tumor cell growth and promotes tumor cell death despite the presence of mutations in multiple other genes. Lee, Gene Therapy, 324 in Pass, Lung Cancer: Principles and Practice (2000).

"In NSCLC it was initially shown that introduction of a vector containing the wt-53 (wild type) into cell lines, which {had} either a deletion or a missense mutation in p53, markedly reduced cell proliferation and tumorigenecity." Fredericksen, Gene Therapy for Lung Cancer, Lung Cancer, Vol. 23 (3) (1999) pp. 191-207.

1.68 Clinical Trials and Other Research on Humans

1.68.1 Presence of P53 Correlated with Survival

"Presence of p53 antibodies in sera before of during/after radiation therapy can predict increased survival in patients with non-small cell lung cancer." P53 auto-antibodies in non-small cell lung cancer patients can predict increased life expectancy after Radiotherapy," Anticancer Res 1998 May-Jun;18(3B):1999-2002

Some limited, promising results have been seen in P-53 clinical trials.

Here is one description: "In the protocol, tumor regression was observed in three out of seven patients. In two patients, postreatment biopsies taken 4 weeks after injection with the retrovirus (P53 wild type) showed no evidence of viable tumor." However, the patients involved in the trial died, with the inhibition of the tumor apparently too late. Fredericksen, Gene Therapy for Lung Cancer, Lung Cancer, Vol. 23 (3) (1999) pp. 191-207.

1.682 Problems and Hurdles to Successful Treatment

It is difficult to repair the gene, the solution being studied is transferring another P-53 gene to the cancer area. Lee writes:

"The complexities of the three-dimensional structure of the p53 tumor-suppresor gene product and the radical changes in this structure induced by a single point mutation makes it extremely difficult to restore its function with pharmaceuticals. Thus, the basic concept of tumor suppressor gene therapy utilizing p53 is to reintroduce a functionally active copy of the defeicte genes in the cancer cell by direct gene transfer to directly induce cell death by apotosis. Lee, id at 324."

Getting enough P-53 to the tumor to have significant results is difficult:

"In all of these studies, it has been difficult to deliver reconbitant virus into solid tumors so as to transduce a significant fraction of the tumor cells, and the effect is limited to the injected nodule, which may be of limited real clinical benefit." Lee, at 324. 

1.7 CURRENT RATIONALE OF CLINICAL TRIALS COMBINING ANTI-ANGIOGENEIC DRUGS WITH CHEMOTHERAPY

Current thinking is to combine anti-angiogenetic drugs with standard forms of chemotherapy. In particular, test standard chemotherapy, for example carboplatin and taxol, against chemotherapy with a particular anti-angiogenic drug. Here are some of the reasons for this approach:

1) Anti-angiogenic drugs do not appear to be sufficiently powerful to combat metastatic lung tumors on their own. There is a roughly 25% success rate in significantly reducing tumors with chemotherapy, which anti-angiogenic treatments are unlikely to replicate, much less beat. For a drug to be FDA approved, it must be at least as useful as standard treatment, and stage 3 clinical trials generally compare the new treatment with the current standard.

2) Anti-angiogenic drugs work in different ways than chemotherapy, so hopefully, they can improve the success rate of chemotherapy.

3) Side effects have been mild, so adding them to chemotherapy should not present substantial health problems.

SOURCES AND REFERENCES

Lung Cancer Online, www.lungcanceronline.org/agents.htm#I, an excellent source, for information about angiogenesis and other topics.

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