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New Targets and New Drugs
A Double Assault on Acute Promyelocytic Leukemia (APL)
Dr. G. de Thé,[1] of St. Louis Hospital in Paris, France, reviewed the single-agent successes of both retinoic acid and arsenic trioxide in first-line and relapsed APL. He then highlighted data generated from animal models that demonstrate a profound synergistic benefit from a combination of retinoic acid and arsenic trioxide treatment, following bone marrow transplant.
Survival in each of the animal models studied was 9 months, compared with 12 days median survival in untreated animals. Median survival was longer for those treated with retinoic acid than for those receiving arsenic trioxide, but was considerably less than half that observed with combination therapy, thus indicating that the effects of arsenic and retinoic acid were synergistic. Moreover, the PML-RAR-alpha fusion protein was eradicated in all animals treated with both agents. These data are provocative, mirroring ongoing findings among American investigators.
Targeting Immortal Cells
While all clinical cancer research, to some extent, is directed at terminating growth of immortal malignant cells, the pathways to achieve this end are numerous, complicated, and unique. The focus of much clinical research is, and has been, to elaborate the very nature of these pathways. Dr. D. Peeper,[2] of The Netherlands Cancer Institute in Amsterdam, The Netherlands, focused on newly identified genes that allow cells to escape from normal senescent apoptosis. Ideally, senescence operates by limiting the proliferative capacity of cells while, at the same time, preventing cellular transformation.
Both p19ARF and p53 are well-known tumor suppressor genes whose mutations allow for cellular immortalization. These tumor suppressor genes are under the control of RAS, which must bind GTP in order to achieve activation. Mutations in the RAS oncogene enable RAS to be activated without GTP binding. Such mutations also prevent RAS deactivation by GTPase.
Peeper and colleague created a temperature-sensitive mouse fibroblast cell line immortalized by the large T antigen. Testing a retroviral cDNA expression library after shifting cells to an unfavorable temperature, they were able to identify several genes that prevent cellular senescence, including TBX-3 and BCL6, 2 genes frequently activated in human lymphomas.
Using this same expression library to analyze the effects of introducing activated RAS-V12 into immortalized fibroblasts, other genes, including DRIL-1, were found to confer resistance to cellular senescence. DRIL-1 was shown to work independently of p19ARF and p51. Peeper surmised that DRIL-1 may work by activating another tumor suppressor gene, p16, which, interestingly, is found in the same gene locus as p19. DRIL-1 is also associated with increased cyclin E expression, which also appears to bypass RAS-induced senescence. DRIL-1 has subsequently been identified in a subset of human cancer lines. The translational research that may ensue from such work is considerable.
Dr. S. Lain, from the Ninewells Hospital and Medical School in Dundee, United Kingdom, further characterized the activity of the p53 tumor suppressor gene, discussing some aspects of drugs that target p53.[3] The importance of p53 has been shown in knock-out mice studies in which the loss of wild-type p53 leads to increased tumor growth.
The Li-Fraumeni syndrome (multitumor development with loss of p53 suppression), characterized by the absence of wild-type p53, and the presence of p53 mutations in approximately 50% of human cancer cell lines, further attests to the role of p53 in the process of tumorigenesis.
It is believed that p53 operates as a transcription activator, inducing expression of p21 (associated with promoting cell cycle arrest) and Bax (implicated in the promotion of apoptosis). Loss of p53 function would thus promote cell immortalization. Normal cells contain low levels of p53.
Overexpression of other genes, like Mdm2, may affect p53 by interfering with the translational machinery of p53. Moreover, Mdm2 upregulates E3 ligase activity, resulting in proteosome degradation of p53. In certain tumors that overexpress Mdm2, the need of p53 gene mutation is thus bypassed. This may account for why tumors can still arise in individuals with wild-type p53. Another indirect brake to p53 activity has been shown in patients whose cells are deficient for the p14ARF tumor suppressor, a natural inhibitor of Mdm2.
These concepts give credence to the notion of developing nongenotoxic methods of activating the p53 response. Conceivably, one could suppress Mdm2 with antisense inhibition or with transcription inhibitors, particularly in the presence of wild-type p53. The interaction between p53 and Mdm2 can be inhibited by antibodies or peptide fragments that mimic p19ARF.
P19ARF overexpression (or peptides that mimic p19) also inhibit the ability of Mdm2 to transport the p53/Mdm2 complex from the cell nucleus to the cytoplasm. And, finally, the inhibition of Mdm2-mediate proteosome degradation of p53 by p19ARF or by p19ARF analogues can preserve wild-type p53 activity.
The last 3 concepts have been tested in human neural fibroblasts (HNF) using leptomycin B (LMB). Besides inducing p53 transcriptional activity, LMB arrests HNF proliferation. These effects were reversed with the addition of Mdm2. LMB also showed activity in suppressing the proliferation of human papilloma virus-infected cervical cancer cells, in combination with microscopic amounts of actinomycin D. In the process, p53 activity was upregulated, although the precise mechanism of action was not elucidated.
Targeting Tyrosine Kinase: The STI571 Story
In spite of its relative newness, STI571 has already developed the cachet of a time-tested therapy in treating chronic myeloid leukemia (CML). Dr. A. Matter summarized the history of STI571 from conceptualization to clinical use, reminding us that its development came about as a result of basic science being translated into the clinical arena.
CML was selected as a potential disease for targeted therapy because of the presence of the Philadelphia chromosome in greater than 95% of cases with constitutive activation of the tyrosine kinase activity of Abl, required for CML transformation.
Working with the lead structure of protein kinases, basic scientists then developed more than 300 compounds designed to inhibit this enzymatic structure. It was known that most of these compounds inhibited both protein kinase C (PKC) as well as tyrosine kinase. Subsequently, much effort was expended on abolishing PKC activity. The addition of a methyl group seemed to preserve the differentiation of this nonmutagenic agent, but only after creation of a salt formulation was the issue of low solubility ameliorated, allowing for oral drug bioavailability.
What followed was a flurry of studies, beginning in 1996, demonstrating cellular selectivity of STI571,[4] followed by data in animal models, and eventually human clinical trials, in which complete remissions were reported in 53 of 54 patients treated.[5] Activity was demonstrated in chronic as well as in accelerated and blast phase CML, and significant cytogenetic responses were recorded (Table).[5]
Disease
Response Rate
Cytogenetic Responses
CML chronic phase
89%
55%
CML accelerated phase
68%
23%
CML blast phase
29%
15%
CML, chronic myeloid leukemia
Since the publication of these data, several patients have relapsed, triggering investigations regarding mechanisms of resistance, linked to the BCR-Abl gene amplification, gene mutations, development of multidrug resistance (MDR) via drug efflux and drug inactivation, and activation of pathways downstream of BCR-Abl.
Other tumor targets for STI571 have since been identified, including gastrointestinal stromal tumors (GISTs), small-cell lung cancers, and certain types of acute myeloid leukemia, all of which express c-kit. Interesting data were presented at this year's American Society of Clinical Oncology meeting in San Francisco, California, describing the remarkable efficacy of STI571 in treating heretofore untreatable GISTs.[6,7] An ongoing investigation has enrolled 100 patients with GISTs, two thirds of whom have achieved major responses.
Activity to STI571 has also been found in tumors expressing platelet-derived growth factor receptor, including gliomas, chronic myelomonocytic leukemias, and bone metastases from both prostate and breast cancer primaries.
New Avenues
As the STI571 story continues to unfold, other investigators seek to identify newer targets and newer drugs with potential clinical efficacy. Phase 1 trials incorporating some of these new agents were highlighted in subsequent abstracts and oral presentations. A rapamycin derivative, CCI-779, has shown antitumor activity in combination with 5-fluorouracil and leucovorin,[8] while PKC412, a PKC inhibitor, when combined with 5-fluorouracil and leucovorin, has produced responses in previously untreated patients with metastatic colorectal cancer.[9]
Exisulind and CP461, both part of a drug class known as selective antiapoptotic antineoplastic drugs, independently of COX 1, COX 2, p53, BCL-2, or other well-characterized cell cycle arrestors, have demonstrated synergistic cytotoxicity in combination with trastuzumab and/or taxanes against human breast cancer cell lines.[10]
ZD8339, an oral, selective, epidermal growth factor receptor tyrosine kinase inhibitor, when combined with gemcitabine and cisplatin, has shown activity against a number of tumor types, including nonsmall-cell lung cancer, adenocarcinoma of unknown primary, esophageal, and other tumors.[11] A 3-arm phase 3 trial evaluating this combination has recently completed accrual of more than 1000 patients with advanced nonsmall-cell lung cancer.
Aplidine, a marine-derived cyclodepsipeptide that blocks cell cycle progression at G1, in an MDR/p53 independent fashion, seems to decrease the expression of vascular endothelial growth factor (VEGF) secretion and VEGF-receptor expression, exerting antitumor activity in medullary thyroid, renal cell, neuroendocrine, and melanoma tumors.[12]
It remains to be seen which, if any, of these compounds will distinguish themselves from the countless other new agents under study. Yet, a certain confidence can be derived just by the fact that so many novel approaches are being pursued. Something important is bound to turn up!
References
De Thé G. Retinoic acid and arsenic in acute premyelocytic leukemia. Eur J Cancer. 2001;37(suppl 6):13. Abstract 47.
Peeper D. Genes that allow escape from senescence. Eur J Cancer. 2001;37(suppl 6):13. Abstract 48.
Lain S, Lane D. Drugs targeting p53 regulatory mechanisms. Eur J Cancer. 2001;37(suppl 6):13. Abstract 50.
Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566.
O'Dwyer ME, Druker BJ. Status of bcr-abl tyrosine kinase inhibitors in chronic myelogenous leukemia. Curr Opin Oncol. 2000;12:594-597.
Blanke CD, von Mehren M, Joensuu H, et al. Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI571, in patients with unresectable or metastatic gastrointestinal stromal tumors (GISTs) expressing c-kit (CD117). 37th Annual Meeting of the American Society of Clinical Oncology; May 12-15, 2001; San Francisco, California. Abstract 1.
Van Oosterom AT, Judson I, Verwej J, et al. STI571, an active drug in metastatic gastrointestinal stromal tumors (GIST), an EORTC Phase I study. 37th Annual Meeting of the American Society of Clinical Oncology; May 12-15, 2001; San Francisco, California. Abstract 2.
Punt CJA, Bruntsch U, Hanauske AR, et al. A phase I study of escalating doses of CCI-779 in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Eur J Cancer. 2001;37(suppl 6):17. Abstract 53.
Weigang Kohler K, Bouterfa H, Bruntsch U, et al. A phase I trial of PKC412, an inhibitor of protein kinase C, in combination with bolus 5-fluorouracil and leucovorin in patients with stage IV colorectal cancer. Eur J Cancer. 2001;37(suppl 6):17. Abstract 54.
Pegram M, Liu L, Lloyd M, et al. Exisulinds and CP461 inhibit cell growth, induce apoptosis and have synergy with herceptin and taxotere in breast cancer cells. Eur J Cancer. 2001;37(suppl 6):30. Abstract 100.
Giaccone G, Gonzales-Larriba JL, Smit EF, et al. ZD1839 (Iressa), an orally-active, selective epidermal growth factor receptor tyrosine kinase inhibitor (egfr-tki) is well tolerated in combination with gemcitabine and cisplatin in patients with advanced solid tumors: preliminary tolerability, efficacy and pharmacokinetic results. Eur J Cancer. 2001;37(suppl 6):30. Abstract 102.
Raymond E, Paz-Ares L, Izquierdo, et al. Phase I trial with aplidine, a new marine anticancer compound. Eur J Cancer. 2001;37(suppl 6):32. Abstract 107.
Source: Medscape
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