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February 2007

Understanding GIST survival under imatinib treatment

One of the goals of Life Raft Group research team is to investigate the underlying mechanisms leading to the differences in diverse degree of response to imatinib mesylate treatment. Indeed, while 80 to 85 percent of patients with advanced GISTs show an initial benefit from the treatment, the response level may vary from rapid and gross reduction in tumor volume to no or only minor tumor shrinkage (described as stable disease) (5). Moreover, the heterogeneous type of response from patients carrying multiple nodules is sometimes observed, with certain lesions responding well and some being stable (2, 13). Importantly, the clinical and pathologic complete response is exceedingly rare (3, 4, 11).

The information on the histopathological changes (histopathology is the microscopic study of diseased tissue) in patients treated with imatinib is quite limited, but the overall changes in these patients are very similar. A variable, but often prominent loss of tumor cells is seen and this loss is replaced by a dense hyalinization (a change to hyaline; a cartilage-like consistency) and fibrosis (fibrous connective tissue). In addition, areas of stromal hemorrhages and necrosis are present. Proliferation markers are usually decreased but the seemingly microscopically viable foci of tumor cells are variable encountered (13, 16). The degree of response does not correlate with the duration of imatinib therapy, with possible variable grade and heterogeneity of response pattern within different tumor areas or tumor lesions of individual patients (13). In concordance with the histopathological analyses, data from most clinical studies show that many patients responding to imatinib eventually progress, indicating that the effect of the drug on residual GIST cells is rather cytostatic (stopping cell growth and multiplication) than cytotoxic (killing the cell) (2, 5, 15).

Notably, these preliminary scattered histopathological observations were recently further confirmed by the Agaram et al. study (1). The authors investigated the pathologic response and molecular changes in a largest so far analyzed group of clinically responsive or stable GIST lesions removed by elective surgery. Since the predominant mechanism of acquired resistance to imatinib is via additional mutations in KIT, the authors tried to answer the question whether the secondary mutations are present in GIST cells that are stable under imatinib pressure (which could provide a survival advantage to the tumor cells and which could render the tumor only partially sensitive to the drug). In addition, for the first time the molecular signatures of imatinib-stable/imatinib-responsive lesions were established by the expression profiling study.

 

The results of this study can be summarized in a few points:
1) The histologic response to imatinib is heterogeneous and does not correlate well with clinical response or imatinib therapy duration.
2) High-abundant, second-site KIT mutations are rare in imatinib-responsive GISTs compared with imatinib-resistant tumors.
3) Proliferation capacity of tumor cells (which correlate with mitotic activity) does not correlate with the KIT genotype or overall response of the tumor to imatinib therapy. Even in tumors with a very good histologic response, small foci of distinctly viable tumor, which were mitotically active, could be identified.
4) Activation of KIT and downstream targets (such as PI3-K, AKT, mTOR, MAPK, and ribosomal S6) was consistent in all tumors analyzed. The temporary cessation of the drug before surgical resection (one to two days before surgery) most likely was a confounding factor for this observation.
5) The gene signature of imatinibresponse in GISTs showed downregulation of cell cycle control regulators as well as up-regulation of genes involved in muscle differentiation and function.

The most important message from the aforementioned study is confirmation that although imatinib treatment induces apoptosis (a type of cell death) and causes cell cycle arrest of GIST cells, some residual cells usually survive and become active again within a remarkably short time after cessation of treatment. Therefore, either a combination or novel systemic therapeutic approaches are needed to maximize GIST cell death.

Cancer is a manifestation of six essential alterations in cell physiology that collectively dictate malignant growth: 1) self-sufficiency in growth signals, 2) insensitivity to growth-inhibitory (antigrowth) signals, 3) evasion of programmed cell death (apoptosis), 4) limitless replicative potential, 5) sustained angiogenesis, and 6) tissue invasion and metastasis (9, 10).

Impaired apoptosis signaling is common in cancer cells and plays an important role in tumor initiation, progression and metastasis, as cells with genomic damage or deregulated cell cycle are normally eliminated by apoptosis (6, 7, 8). Resistance of cancer cells to apoptosis is especially deleterious, because it results in a higher survival capacity under adverse conditions, enhancing the malignant potential of the tumor, favoring accumulation of mutations, metastasis and rendering tumor cells resistant to therapy as well as to host defense mechanisms.

Cancer cells invent numerous ways to inactivate the apoptotic machinery in order to survive and thrive. Included among these are the activation of PI3-K and AKT firing, the increase in the levels of anti-apoptotic BCL-2-related proteins, the inactivation of p53 protein through changes in the p53 gene, interference with cytochrome c release from mitochondria, and inhibition of caspases (which are enzymes that initiate cell death process) (10).

Mammals have evolved a receptor/ ligand mechanism that enables the organism actively to direct individual cells to self-destruct through the presence of cell surface death receptors, which transmit apoptosis signals initiated by specific death ligands (7, 12). Apoptosis- targeted therapy through activation of death receptors can engage an apoptotic response that bypasses the action of sensors, such as p53, and therefore their frequent mutant state in cancer should be irrelevant to this therapeutic approach. Death receptors are members of the tumor necrosis factor (TNF) receptor gene superfamily, which consists of more than 20 proteins with a broad range of biological function, including the regulation of cell death and survival, differentiation or immune regulation (7). The best-characterized death receptors in their potential to induce apoptosis are Fas, TNF receptor 1 (TNFR1), and TNFrelated apoptosis-inducing ligand (TRAIL) receptors (death receptor 4/ DR4 and death receptor 5/DR5). Hence, the corresponding death ligands TNF, Fas ligand (FasL) and TRAIL are interesting candidates for antitumor therapy (12, 14, 17). Targeting death receptors, such as Fas, is a promising anticancer strategy by which apoptotic cell death can be induced. It is expected that already existing small molecules targeting these death receptors will be designed to lower toxicity and increase antitumor activity.

References

1. Agaram NP, Besmer P, Wong GC, Guo T, Socci ND, Maki RG, DeSantis D, Brennan MF, Singer S, DeMatteo RP, Antonescu CR. Pathologic and Molecular Heterogeneity in Imatinib-Stable or Imatinib-Responsive Gastrointestinal Stromal Tumors. Clin Cancer Res 2007;13(1): 170-181

2. Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B, Leversha MA, Jeffrey PD, Desantis D, Singer S, Brennan MF, Maki RG, DeMatteo RP. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005; 11:4182- 4190

3. Bauer S, Hartmann JT, de Wit M et al. Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib. Int J Cancer 2005; 117:316-325

4. Chacon M, Roca E, Huertas E, et al. CASE 3. Pathologic complete remission of metastatic gastrointestinal stromal tumor after imatinib mesylate. J Clin Oncol 2005; 23:1580-1582

5. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol 2004; 22:3813- 3825.

6. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004; 116:205-219

7. Debatin KM, Krammer PH. Death receptors in chemotherapy and cancer. Oncogene 2004; 23:2950-2966

8. Green DR, Evan GI. A matter of life and death. Cancer Cell 2002; 1:19-30

9. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57-70

10. Igney FH, Krammer PH. Death and anti-death: tumour resistance to apopthosis. Nat Rev Cancer 2002; 2:277-288

11. Melichar B, Voboril Z, Nozicka J, Ryska A, Urminska H, Vanecek T, Michal M. Pathological complete response in advanced gastrointestinal stromal tumor after imatinib therapy. Internal Medicine 2005; 44:11

12. Mollinedo F, Gajate C. Fas/CD95 death receptor and lipid rafts: New targets for apoptosis-directed cancer therapy. Drug Resist Update 2006; 9:51-73

13. Raut CP, Posner M, Desai J, Morgan JA, George S, Zahrieh D, Fletcher CD, Demetri GD, Bertagnolli MM.Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 2006; 24:2325-31

14. Shankar S, Srivastava RK. Enhancement of therapeutic potential of TRAIL by cancer therapy and irradiation: mechanisms and clinical implications. Drug Resist Update 2004; 7:139- 156

15. Sciot R, Debiec-Rychter M. GIST under imatinib therapy. Semin Diagn Pathol 2006; 23(2):84-90.

16. Wardelmann E, Thomas N, Merkelbach-Bruse S, Pauls K, Speidel N, Buttner R, Bihl H, Leutner CC, Heinicke T, Hohenberger P. Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations. Lancet Oncol 2005; 6:249- 251

17. Van Geelen CMM, de Vries EGE, de Jong S. Lessons from TRAILresistance mechanisms in colorectal cancer cells: paving the road to patienttailored therapy. Drug Resist Updat 2004; 7:345-358

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