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© 2000 American Society for Clinical Oncology
Plasma MMPs as Surrogates of Bay 12-9566Veterans Administration Medical Center NorthportNY State University of New York at Stony Brook Stony Brook, NY To the Editor:Clinical testing of antimetastatic and antiangiogenic drugs in patients with cancer has created new challenges for medical oncologists. Therapeutic principles used in the design of protocols for cancer cytotoxic agents are not necessarily appropriate. Translational researchers need to develop additional tools to examine the effectiveness of these new drugs.1 Rowinsky et al2 in the January issue of the Journal of Clinical Oncology reported a phase I/pharmacologic study of the matrix metalloproteinase (MMP) inhibitor BAY 12-9566 in patients with advanced cancer. As stated by the authors, "one goal was to determine whether BAY 12-9566 affects plasma concentrations of MMP-2, MMP-9, and tissue inhibitor of MMP-2 (TIMP-2). ...Hypothetically, such markers may be used to monitor MMP activity, determine the optimal dose schedule of MMP inhibitors, detect disease progression, and quantify responsiveness to therapy." While Rowinsky et al2 are to be applauded for their efforts to identify surrogate plasma markers for assessing MMP inhibitor activity, several basic flaws in their report need to be addressed. Terminology. TIMP-2 is not the abbreviation for tissue inhibitor of MMP-2. TIMP-2 was so named because it was the second tissue inhibitor of MMPs discovered; subsequently, TIMP-3 and TIMP-4 have been identified. TIMP-2 is an effective inhibitor of almost all MMPs, not just MMP-2.3 In regard to the current report, it is not clear why TIMP-2, which is constitutively produced, was selected for plasma measurement in cancer patients rather than TIMP-1, which is present in higher concentrations in blood and is induced by cytokine stimulation. Surrogate markers to monitor MMP activity. The decision to measure activated MMP-9 in plasma flies in the face of the established principle that the overabundance of highly efficient MMP inhibitors in tissues (TIMP-1 and -2) will rapidly bind to activated MMPs even before the MMPs seep into the blood stream.4 A more fruitful approach may have been to develop an assay sufficiently sensitive to quantify the plasma level of MMP-9/TIMP-2 complexes because activated but not latent MMP-9 binds to TIMP-2, thereby reflecting the level of activated MMP-9 in tissues. The plasma MMP-9:TIMP-1 complex that we have described as being of prognostic significance in colon cancer is a complex of latent MMP-9 with TIMP-1.5 Other potential surrogate markers for activated MMPs include the identification of the N-terminal propeptide of MMPs cleaved during the activation process or degradation products of extracellular matrix proteins specifically attacked by activated metalloproteinases (ie, aggrecan cleavage products6). Unfortunately, these assays remain to be developed. Detection of disease progression. Rowinsky et al2 reported that inconsistent variability in plasma MMP-9 was noted in cancer patients. It needs to be emphasized that plasma levels of MMPs reflect contributions from diffuse body sources, not just cancer tissue. In fact, it is our experience that plasma levels of MMP-9 measured over prolonged periods in patients with advanced cancer fluctuate widely, often unrelated to progression of disease (data not shown). Clinical trial design. A basic issue that is addressed in designing phase II/III trials of antimetastatic drugs deals with which experimental indicators are useful for selecting a specific type of malignancy for inclusion in a clinical trial. With cytotoxic chemotherapeutic agents, in vitro drug testing using cancer cell lines and in vivo tumor transplantation models provides useful information. These approaches are of questionable benefit with MMP inhibitors because the MMPs in cancer are primarily synthesized by peritumoral stromal cells rather than the cancer cells themselves.1 Whereas tumor response measured in terms of shrinkage of tumor size in phase I cytotoxic drug trials provides important clues for identifying responsive cancers, this approach is less useful with antimetastatic agents where the goal is long-term prevention of tumor progression/dissemination. In regard to the recent decision of the Bayer Corporation to terminate the clinical trial of BAY 12-9566 in patients with small-cell lung cancer,7 the scientific literature provided little support for the concept that this cancer type was a good target for a drug with MMP inhibitory activity. REFERENCES 10. Zucker S: Experimental models to identify antimetastatic drugs: Are we there yet? Ann N Y Acad Sci 878:208-211, 1999[Medline]
10.
Rowinsky WK, Humphrey R, Hammond LA, et al: Phase I and pharmacologic study of the specific matrix metalloproteinase inhibitor BAY 12-9566 in a protracted oral daily dosing schedule in patients with solid malignancies. J Clin Oncol 18:178-186, 2000 10. Willenbrook F, Crabbe T, Slocombe PM, et al: The activity of the tissue inhibitors of metalloproteinase is regulated by C-terminal domain interactions: A kinetic analysis of the inhibition of gelatinase A. Biochemistry 32:4330-4337, 1993[Medline] 10. Zucker S, Hymowitiz M, Conner C, et al: Measurement of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in blood and tissues. Ann N Y Acad Sci 878:212-227, 1999[Medline] 10. Zucker S, Lysik RM, DiMassimo BI, et al: Plasma assay of gelatinase B: Tissue inhibitor of metalloproteinase (TIMP) complexes in cancer. Cancer 76:700-708, 1995[Medline] 10. Hughes CE, Caterson B, Fosang AJ, et al: Monoclonal antibodies that specifically recognize neoepitope sequences generated by "aggreacanase" and matrix metalloproteinase cleavage of aggrecan: Application to catabolism in situ and in vitro. Biochem J 305:799-804, 1995 10. Bayer Corporation: Bayer halts clinical trials evaluating MMPI. Bayer Corporation News Release. Http://www.bayerus.com/new/1999/09.99ud.html
University of Colorodo Cancer Center DenverCO In Reply:Dr Zucker raises several important issues regarding the optimal use of biologic assays during clinical trials of matrix metalloproteinase (MMP) inhibitors. To date, the incorporation of such assays into clinical trials has been inconsistent and poorly documented. These efforts have also been disorganized, with minimal attempts to validate the assays before clinical development. Although we agree with most of the points made by Zucker, several issues must be clarified. With regard to the terminology used for TIMP-2, we apologize for the error in the abstract that refers to TIMP-2 being the tissue inhibitor of MMP-2. We understand the complexity of TIMP-2 in regulating the activity of MMPs other than MMP-2; however, the literature does support the important role of TIMP-2 in complexing with MMP-2.1,2 In retrospect, although it would have been perhaps more revealing to examine TIMP-1 in the plasma of patients on this trial, the commercial kit for this assay had not been fully developed and validated at the time of the clinical trial. The measurement of active MMP-9 in the study reflected both circulating active MMP-9 and pro-MMP-9 and was based upon similar studies using zymography in clinical trials of marimastat 3. Since the predominant effect of BAY 12-9566 is on the function, and not on the synthesis, of MMPs, we thought it would be worthwhile to determine whether the proportion of potentially functional, circulating MMP-9 decreased over time. In response to the comment about fluctuating plasma concentrations of MMP-9 in cancer patients, we agree that the measurement of plasma MMP-9 is problematic; however, our decision to measure circulating MMP-9 was based upon the prevailing literature and the availability of a well-validated and feasible assay at the time of clinical development. In fact, numerous reports, including those of Zucker et al, have reported elevated plasma concentrations of MMP-2 and/or MMP-9 in patients with cancer.4-6 Although we agree that it may be imprecise to assume that circulating MMP concentrations reflect contributions from diverse tissue sources, further investigations in this area are clearly necessary. While Zucker suggests using alternate, more direct assays, he also notes that such assays "remain to be developed." Finally, the need to develop appropriate clinical trial designs for these types of agents is well recognized by the clinical oncology community. We believe that is imperative that investigators involved in basic research in MMPs, tumor angiogenesis, and signal transduction, as well as the pharmaceutical industry sponsors of specific therapeutics in clinical trials, devote a significant portion of their preclinical efforts to investigating the use of biologic markers and to developing and validating practical assays that truly reflect the actions of these therapeutics at the tumor target before clinical development. Although it is clear that such strategies will result in the most expedient and fruitful clinical research efforts, there is a paucity of such investigations relative to the large number of such compounds entering clinical trials. The lack of organized efforts toward the development and validation of biologic assays and markers that can readily be used in the clinic, beginning before clinical development, will undoubtedly lead to wasted clinical resources, wasted time, and further delays in the evaluation of many novel classes of targeted therapeutics. REFERENCES
11.
Howard EK, Bullen EC, Banda MJ: Regulation of the autoactivation of human 72-kDa progelatinase by tissue inhibitor of metalloproteinases-2. J Biol Chem 266:13064-13069, 1991
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Strongin AY, Marmer BL, Grant GA, et al: Plasma membrane-dependent activation of the 72-kDa type IV collagenase is prevented by complex formation with TIMP-2. J Biol Chem 268:14033-14039, 1993 11. Wojtowicz-Praga S, Torri J, Johnson M, et al: Phase I trial of marimastat, a novel matrix metalloprotease inhibitor, administered orally to patients with advanced lung cancer. J Clin Oncol 16:2150-2156, 1998[Abstract]
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Zucker S, Lysik RM, Zarrabi MH, et al: M(r) 92,000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. Cancer Res 53:140-146, 1993
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Iizasa T, Fujisawa T, Suzuki M, et al: Elevated levels of circulating plasma matrix metalloproteinase 9 in non-small cell lung cancer patients. Clin Cancer Res 5:149-153, 1999 11. Endo K, Maehara Y, Baba H, et al: Elevated levels of serum and plasma metalloproteinases in patients with gastric cancer. Anticancer Res 17:2253-2258, 1997[Medline]
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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