Current Clinical Trials of Molecularly Targeted Agents in Children With Cancer

March 1, 2002

A number of molecularly targeted agents directed at critical pathways involved in cell survival and cell proliferation have recently entered clinical evaluation in children with cancer. These agents offer the potential for more effective anticancer therapy while diminishing acute and long-term toxic effects. Systematic evaluations of agents such as these are essential if continuing improvements in outcome are to be achieved in children with cancer. Brief summaries of the rationale for conducting studies of several agents in children are provided below. Following these summaries is a listing of phase I, phase I/II, phase II, and pilot studies of these agents in pediatric populations

A number of molecularly targeted agents directed atcritical pathways involved in cell survival and cell proliferation have recentlyentered clinical evaluation in children with cancer. These agents offer thepotential for more effective anticancer therapy while diminishing acute andlong-term toxic effects. Systematic evaluations of agents such as these areessential if continuing improvements in outcome are to be achieved in childrenwith cancer. Brief summaries of the rationale for conducting studies of severalagents in children are provided below. Following these summaries is a listing ofphase I, phase I/II, phase II, and pilot studies of these agents in pediatricpopulations.

Farnesyltransferase Inhibitors R115777 and SCH66336

Two farnesyltransferase inhibitors (FTIs) are in clinical evaluation inchildren with cancer: R115777 (Janssen Pharmaceutica, Inc) and SCH66336(Schering-Plough, Ltd). Although FTIs were initially developed to inhibit cancercell growth by blocking farnesylation of Ras and preventing its requiredlocalization to the plasma membrane,[1,2] it is increasingly apparent thatinhibition of farnesylation of other proteins may contribute to thegrowth-inhibitory effects of FTIs.[3,4] FTIs show in vitro activity against arange of tumor cell lines.[2,4] The in vivo antitumor activity of FTIs(including regression of some tumors) has been observed against a number oftumor types, including Bcr-Abl-expressing leukemias,[5,6] glioma,[7]pancreatic,[4,8] colorectal cancers,[4] and melanoma.[4]

Clinical Trials Referral Resource is designed to serve as a ready reference for oncologists to help identify clinical trials that might be suitable for their patients. We hope it will also enhance accrual to clinical trials by informing practicing oncologists of ongoing protocols. Currently in the United States less than 10% of eligible adult patients are entered into clinical trials. The result is a delay in answering important therapeutic and scientific questions and disseminating therapeutic advances to the general oncology community.

It should be emphasized that including a specific trial does not imply that it is more important than another trial. Among the criteria for selection are that the trial is addressing an important question and is not expected to close in the immediate future (less than 1 year), and that initial staging or laboratory tests required for patient eligibility are widely practiced and available. Information on other protocols can be accessed via Physician’s Data Query (PDQ).*

We emphasize that this is an attempt to encourage referral of patients to these trials. We are specifically not soliciting additional members for the cooperative groups, nor are we suggesting how practicing oncologists should be treating patients who are not in a study.

This month’s installment of Clinical Trials Referral Resource is devoted to current clinical trials of molecularly targeted agents for children with cancer.

For patient entry information, see the individual trials.

* PDQ is a comprehensive database service provided by the National Cancer Institute’s International Cancer Information Center and Office of Cancer Communications for retrieval of cancer treatment information, including peer-reviewed statements on treatment options, supportive care, screening, and prevention; and an international clinical trials registry. For more information on PDQ, online access is available at, or contact the Cancer Information Service offices (1-800-4-CANCER).

R115777 is an orally administered FTI that has been studied in phase I trialsin adults and children.[9] Multiple schedules have been evaluated in adults, butin children the primary schedule studied has been twice daily dosing for 21 daysevery 4 weeks.[10] In the pediatric solid tumor phase I trial, the maximumtolerated dose was 200 mg/m2, and dose-limiting toxicities at higher dosesincluded grade 4 neutropenia, grade 3/4 thrombocytopenia, grade 3 rash,hypofibrinogenemia, vomiting, and diarrhea.[10]

R115777 was studied in a phase I trial in adults with refractory and relapsedleukemia using the twice-daily-for-21-days schedule.[11] Dose-limiting toxicityoccurred at 1,200 mg bid with central neurotoxicity evidenced by ataxia,confusion, and dysarthria. Clinical responses occurred in 10 (29%) of the 34evaluable patients, including 2 complete remissions. R115777 also inducedresponses in adult patients with chronic myelogenous leukemia (CML)[12] andmyelodysplastic syndrome.[13]

SCH66336 has been studied in phase I trials in adults using a variety ofschedules.[9] For continuous daily oral administration, the recommended phase IIdosage in adults is 200 mg bid,[14] with higher doses causingmyelosuppression and neurotoxicity (confusion and disorientation). For bothR115777 and SCH66336, inhibition of protein farnesylation has been demonstratedat doses with tolerable toxicity.[10,11,15]

R115777 is under evaluation in children with juvenile myelomonocytic leukemia(AAML0122). Aberrant regulation of the Ras pathway, either by Ras-activatingmutations[16] or by inactivating mutations of neurofibromin,[17] ischaracteristic of some cases of juvenile myelomonocytic leukemia. Supportingevaluation of an FTI against juvenile myelomonocytic leukemia is the observationthat cells of this disease cultured in vitro show greater sensitivity toFTI-mediated growth inhibition than do normal myeloid precursor cells.[18] Onthe other hand, an FTI produced no apparent antileukemic effect in a transgenicmurine model of juvenile myelomonocytic leukemia based on homozygousneurofibromin deletion.[19] R115777 is also being evaluated in a phase I trialin children with acute leukemias (1930/ADVL0116), based in part on its activityin adults with acute leukemia.[11]

The Pediatric Brain Tumor Consortium is conducting a phase I evaluation ofSCH66336 in children with brain tumors (PBTC-003). The rationale for this studyincludes the significant antiproliferative effects of FTIs against humanmalignant glioma cells[20,21] and the in vivo antitumor activity of FTIs againsthuman glioma xenograft models.[7,21]

FTIs are of interest for patients with neurofibromatosis 1 because mutationsin neurofibromin lead to increased Ras signaling.[22,23] The potentialapplications of FTIs in this patient population include treatment of plexiformneurofibromas [24] and neurofibromatosis 1-associated malignancies.[25] Atrial of R115777 in children and adults with plexiform neurofibromas is ongoing(T99-0090).

Imatinib Mesylate (Gleevec)

Imatinib mesylate (STI571, Gleevec [Novartis]) is the first rationallydesigned molecularly targeted agent approved for a cancer indication. The drugpotently inhibits several tyrosine kinases, including c-Abl, c-Kit,platelet-derived growth factor (PDGF) receptor, and the p210Bcr-Abl andP190Bcr-Abl
fusion proteins associated with Philadelphia chromosome (Ph)-positiveleukemias.[26,27] Imatinib inhibits the growth of cells expressing the
Bcr-Abl fusion protein[26] and induces apoptosis of Bcr-Abl-positivecells,[26] showing activity both in vitro[26,28,29] and in vivo.[26,30]

These preclinical observations have been replicated clinically, with highlevels of antitumor activity observed for patients with chronic phase CMLrefractory to or intolerant of interferon-alpha.[31] Single-agent activity wasalso observed against Ph-positive acute lymphocytic leukemia (ALL) andPh-positive CML in blast crisis, although the response rates were lower and theduration of response relatively short compared to those achieved againstchronic-phase CML.[32] Imatinib is very active against the gastrointestinalstromal tumor, which is associated with activating mutations of the c-Kitreceptor.[33,34]

Bcr-Abl expression inhibits the apoptosis induced by cytotoxic agents,[35-39]and this Bcr-Abl-driven chemoresistance is likely a major cause of the poorsurvival rate of patients with Ph-positive leukemia treated with conventionalchemotherapy agents. Inhibition of Bcr-Abl can reverse drug resistance,[40] andimatinib has been shown to potentiate the activity of cytotoxic agents againstBcr-Abl-expressing cells.[41,42] The concept of combining imatinib with knownactive agents is an important one, because resistance to imatinib as a singleagent can develop by multiple mechanisms, including overexpression of theBcr-Abl fusion protein and mutation of the Bcr-Abl gene.[43-45]

A pediatric phase I study of imatinib in children with Ph-positive leukemia(P9973) has been reported.[46] Imatinib was well tolerated, and its antileukemicactivity in children was similar to that seen in adults. Building upon thisphase I experience, a phase II trial of imatinib in children with CML who arerefractory to or intolerant of interferon-alpha is being conducted (AAML0123).Given the relatively poor prognosis of children with Ph-positive ALL, a highpriority of research in childhood ALL is to define ways in which imatinib canpotentiate the effect of conventional chemotherapy. The AALL0031 pilot studycombines imatinib in 14-day treatment courses with the different chemotherapyblocks used to treat childhood ALL. Recent results from studies in adults withPh-positive ALL support the feasibility of combining imatinib with the intensivechemotherapy regimens used to treat Ph-positive ALL.[47]

Imatinib is also being evaluated in a phase II study in children withselected solid tumors (ADVL0122), based on its ability to inhibit the stem cellfactor/c-Kit pathway and the PDGF/PDGF-receptor pathway. For example, the PDGFligand and receptor have been detected in various pediatric cancers includingosteosarcoma,[48,49] desmoplastic small round-cell tumor,[50, 51] and synovialcell sarcoma.[52] PDGF-C, which also binds to the PDGF-alpha and -betareceptors,[53] has recently been described as a downstream target ofderegulation in EWS-FLI1 transformed cells.[54] c-Kit expression has been notedin Ewing’s Sarcoma,[55] neuroblastoma,[56] and synovial cell sarcoma.[57]

The Pediatric Brain Tumor Consortium is conducting a phase I study ofimatinib in children with high-grade gliomas (PBTC-006). The rationalesupporting this study includes the in vivo activity of the drug againstintracranially implanted brain tumor xenograft models,[58] the expression of thePDGF receptor in a substantial proportion of high-grade gliomas,[59] and theability of imatinib to inhibit PDGF-receptor activation in brain tissue inpreclinical models.[60]

Proteasome Inhibitor PS-341

PS-341 (also known as LDP-341 or MLN-341), a dipeptidyl boronic acid derivative, is apotent proteasome inhibitor.[61,62] PS-341 induces apoptosis in vitro atnanomolar concentrations in a variety of cancer types, including some leukemiacell lines[63,64] and multiple myeloma cells.[65] It is active in vivo as asingle agent against multiple myeloma, prostate, and lung cancer xenograftmodels and is also active against murine squamous cell carcinoma models.[66,67]It enhances the cytotoxic activity of conventional anticancer agents[68-71]and radiation.[68,72] The basis of the antitumor activity of PS-341 and of itsability to enhance the activity of other anticancer treatments may result fromits ability to inhibit nuclear factor (NF)-kappaB activation.[67,69] Otherpotentially relevant biological activities include stabilization of p53, p21WAF/CIP-1, andp27KIP1, inhibition of angiogenesis, and overcoming bcl-2protective functions.[63,67,73-76]

PS-341 has been evaluated in several different schedules, including twiceweekly dosing for 2 weeks (with 1 week’s rest), twice weekly dosing for 4weeks (2 weeks’ rest), twice weekly dosing every other week, and weekly dosingfor 4 weeks (2 weeks’ rest). The recommended phase II dose for these scheduleshas ranged from 1.3 to 1.7 mg/m2.[77] Toxicities that limited dose escalationincluded painful neurosensory toxicity, diarrhea, and fatigue.[77] In phase Istudies, antitumor activity was observed against multiple myeloma, prostatecancer, non-small cell lung cancer, and non-Hodgkin lymphoma.[77-79] A phase IItrial of PS-341 (1.3 mg/m2 per dose twice weekly ´ 2 weeks every 3 weeks) inpatients with multiple myeloma produced high response rates (approximately 50%)in a heavily pretreated population.[80]

A pediatric phase I trial of PS-341 in children with solid tumors is ongoing(ADVL0015). The rationale for evaluating PS-341 in children primarily rests ondata from experiments using other proteasome inhibitors against pediatric tumorsand on data concerning the expression of the NF-kappaB pathway in pediatriccancers. The proteasome inhibitor lactacystin induced differentiation of amurine neuroblastoma cell line (Neu 2A),[81] blocked cell-cycle progression ofhuman osteosarcoma cells in vitro,[81] and induced apoptosis in a Ewing’sSarcoma cell line.[82] A peptidyl aldehyde proteasome inhibitor administered asa single dose induced tumor regression in a murine model of human Burkitt’sLymphoma.[83] The NF-kappaB pathway is activated in leukemia cells from childrenwith ALL[84] and in Reed-Sternberg cells from patients with Hodgkin disease.[85]in the latter setting, NF-kappaB inhibition is sufficient to induceapoptosis.[85,86]

Phase II

Title: Phase II Study of R115777, Isotretinoin, Cytarabine, andFludarabine Followed by Allogeneic Bone Marrow or Umbilical Cord BloodTransplantation in Children With Newly Diagnosed Juvenile MyelomonocyticLeukemia
Protocol Number: COG-AAML0122
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116; for a complete listingof study contacts, click hereLatest Information:

Title: Phase II Study of Imatinib Mesylate in Patients WithPhiladelphia Chromosome Positive Chronic Phase Chronic Myelogenous Leukemia
Protocol Number: COG-AAML0123
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116
Latest Information:

Title: Phase II Study of Imatinib Mesylate in Patients With Relapsedor Refractory Pediatric Solid Tumors
Protocol Number: COG-ADVL0122
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116
Latest Information:

Title: Phase II Randomized Study of R115777 in Pediatric Patients WithNeurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
Protocol Number: NCI-01-C-0222A, NCI-T99-0090
Participating Institutions: National Cancer Institute Pediatric OncologyBranch
Contact: Brigitte C. Widemann, (301) 496-7387; for a complete listingof study contacts, click hereLatest Information:

Phase I/II

Title: A Phase I/II Trial of STI571 in Children With Newly Diagnosed PoorPrognosis Brainstem Gliomas and Recurrent Intracranial Malignant Gliomas
Protocol Number: PBTC-006
Participating Institutions: Pediatric Brain Tumor Consortium
Contact: Ian F. Pollack, (412) 692-5881

Phase I

Title: Phase I Study of R115777 in Pediatric Patients With RefractoryLeukemia
Protocol Number: COG-ADVL0116, NCI-01-C-0196, NCI-1930
Participating Institutions: National Cancer Institute Pediatric OncologyBranch, Children’s Oncology Group
Contact: Brigitte C. Widemann, (301) 496-7387; for a complete listingof study contacts, click hereLatest Information:

Title: Phase I Study of PS-341 in Pediatric Patients With AdvancedSolid Tumors
Protocol Number: COG-ADVL0015
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116; for a complete listingof study contacts, click hereLatest Information:

Title: Phase I Study of SCH 66336 in Children With Recurrent orProgressive Brain Tumors
Protocol Number: PBTC-003
Participating Institutions: Pediatric Brain Tumor Consortium
Contact: Mark W. Kieran, (617) 632-4907; for a complete listingof study contacts, click hereLatest Information:

Pilot Studies

Title: Phase II Pilot Study of Intensified Chemotherapy With orWithout Allogeneic Hematopoietic Stem Cell Transplantation in Children With VeryHigh-Risk Acute Lymphoblastic Leukemia
Protocol Number: COG-AALL0031
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116
Latest Information:

Title: Intensive Induction Therapy for Children With Acute LymphoblasticLeukemia Who Experience a Bone Marrow Relapse
Protocol Number: AALL01P2
Participating Institutions: Children’s Oncology Group
Contact: Judith Everett, (626) 447-0064, ext 116


1. Rowinsky EK, Windle JJ, Von Hoff DD: Ras protein farnesyl transferase: Astrategic target for anticancer therapeutic development. J Clin Oncol17(11):3631-3652, 1999.

2. Eskens FA, Stoter G, Verweij J: Farnesyl transferase inhibitors: Currentdevelopments and future perspectives. Cancer Treat Rev 26(5):319-332, 2000.

3. Omer CA, Chen Z, Diehl RE, et al: Mouse mammary tumor virus-Ki-rasBtransgenic mice develop mammary carcinomas that can be growth-inhibited by afarnesyl:protein transferase inhibitor. Cancer Res 60(10):2680-2688, 2000.

4. End DW, Smets G, Todd AV, et al: Characterization of the antitumor effectsof the selective farnesyl protein transferase inhibitor R115777 in vivo and invitro. Cancer Res 61(1):131-137, 2001.

5. Peters DG, Hoover RR, Gerlach MJ, et al: Activity of the farnesyl proteintransferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia andprimary cells from patients with chronic myeloid leukemia. Blood97(5):1404-1412, 2001.

6. Reichert A, Heisterkamp N, Daley GQ, et al: Treatment of Bcr/Abl-positiveacute lymphoblastic leukemia in P190 transgenic mice with the farnesyltransferase inhibitor SCH66336. Blood 97(5):1399-1403, 2001.

7. Pollack IF, Bredel M, Erff M, et al: Inhibition of Ras and relatedguanosine triphosphate-dependent proteins as a therapeutic strategy for blockingmalignant glioma growth: II—preclinical studies in a nude mouse model.Neurosurgery 45(5):1208-1214, 1999.

8. Liu M, Bryant MS, Chen J, et al: Antitumor activity of SCH 66336, anorally bioavailable tricyclic inhibitor of farnesyl protein transferase, inhuman tumor xenograft models and wap-ras transgenic mice. Cancer Res58(21):4947-4956, 1998.

9. Karp JE, Kaufmann SH, Adjei AA, et al: Current status of clinical trialsof farnesyl transferase inhibitors. Curr Opin Oncol 13(6):470-476, 2001.

10. Widemann BC: Phase 1 trial of R115777, an oral farnesyl transferase (FTASE)inhibitor, in children with refractory solid tumors and neurofibromatosis type 1(NF-1) (abstract). Proc Am Soc Clin Oncol 20:368a, 2001.

11. Karp JE, Lancet JE, Kaufmann SH, et al: Clinical and biologic activity ofthe farnesyltransferase inhibitor R115777 in adults with refractory and relapsedacute leukemias: A phase 1 clinical-laboratory correlative trial. Blood97(11):3361-3369, 2001.

12. Thomas D, Cortes J, O’Brien SM, et al: R115777, a farnesyl transferaseinhibitor (FTI), has significant antileukemia activity in patients with chronicmyeloid leukemia (CML). Blood 98:727a, 2001.

13. Kurzrock R, Cortes J, Rybak ME, et al: Phase II study of R115777, afarnesyl transferase inhibitor, in myelodysplastic syndrome. Blood 98:848a,2001.

14. Eskens F, Awada A, Verweij J, et al: Phase I and pharmacologic study ofcontinuous daily oral SCH 66336, a novel farnesyl transferase inhibitor, inpatients with solid tumors (abstract). Proc Am Soc Clin Oncol 18:156a, 1999.

15. Adjei AA, Erlichman C, Davis JN, et al: A phase I trial of the farnesyltransferase inhibitor SCH66336: evidence for biological and clinical activity.Cancer Res 60(7):1871-1877, 2000.

16. Flotho C, Valcamonica S, Mach-Pascual S, et al: RAS mutations andclonality analysis in children with juvenile myelomonocytic leukemia (JMML).Leukemia 13(1):32-37, 1999.

17. Side LE, Emanuel PD, Taylor B, et al: Mutations of the NF1 gene inchildren with juvenile myelomonocytic leukemia without clinical evidence ofneurofibromatosis, type 1. Blood 92(1):267-272, 1998.

18. Emanuel PD, Snyder RC, Wiley T, et al: Inhibition of juvenilemyelomonocytic leukemia cell growth in vitro by farnesyl transferase inhibitors.Blood 95(2):639-645, 2000.

19. Mahgoub N, Taylor BR, Gratiot M, et al: In vitro and in vivo effects of afarnesyl transferase inhibitor on Nf1-deficient hematopoietic cells. Blood94(7):2469-2476, 1999.

20. Bredel M, Pollack IF, Freund JM, et al: Inhibition of Ras and relatedG-proteins as a therapeutic strategy for blocking malignant glioma growth.Neurosurgery 43(1):124-131, 1998.

21. Feldkamp MM, Lau N, Roncari L, et al: Isotype-specific Ras.GTP-levelspredict the efficacy of farnesyl-transferase inhibitors against humanastrocytomas regardless of Ras mutational status. Cancer Res 61(11):4425-4431,2001.

22. Kim HA, Rosenbaum T, Marchionni MA, et al: Schwann cells fromneurofibromin deficient mice exhibit activation of p21ras, inhibition of cellproliferation and morphological changes. Oncogene 11(2):325-335, 1995.

23. Feldkamp MM, Gutmann DH, Guha A: Neurofibromatosis type 1: Piecing thepuzzle together. Can J Neurol Sci 25(3):181-191, 1998.

24. Feldkamp MM, Angelov L, Guha A: Neurofibromatosis type 1 peripheral nervetumors: Aberrant activation of the Ras pathway. Surg Neurol 51(2):211-218, 1999.

25. Yan N, Ricca C, Fletcher J, et al: Farnesyl transferase inhibitors blockthe neurofibromatosis type I (NF1) malignant phenotype. Cancer Res55(16):3569-3575, 1995.

26. Druker BJ, Tamura S, Buchdunger E, et al: Effects of a selectiveinhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.Nat Med 2(5):561-566, 1996.

27. Beran M, Cao X, Estrov Z, et al: Selective inhibition of cellproliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cellsexpressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor(CGP-57148). Clin Cancer Res 4(7):1661-1672, 1998.

28. Deininger MW, Goldman JM, Lydon N, et al: The tyrosine kinase inhibitorCGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood90(9):3691-3698, 1997.

29. Kasper B, Fruehauf S, Schiedlmeier B, et al: Favorable therapeutic indexof a p210(BCR-ABL)-specific tyrosine kinase inhibitor; activity onlineage-committed and primitive chronic myelogenous leukemia progenitors. CancerChemother Pharmacol 44(5):433-438, 1999.

30. le Coutre P, Mologni L, Cleris L, et al: In vivo eradication of humanBCR/ABL-positive leukemia cells with an ABL-kinase inhibitor [see comments]. JNatl Cancer Inst 91(2):163-168, 1999.

31. Druker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specificinhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl JMed 344(14):1031-1037, 2001.

32. Druker BJ, Sawyers CL, Kantarjian H, et al: Activity of a specificinhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloidleukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. NEngl J Med 344(14):1038-1042, 2001.

33. Demetri GD: Targeting c-kit mutations in solid tumors: Scientificrationale and novel therapeutic options. Semin Oncol 28(5 suppl 17):19-26, 2001.

34. van Oosterom AT, Judson I, Verweij J, et al: Safety and efficacy ofimatinib (STI571) in metastatic gastrointestinal stromal tumors: A phase Istudy. Lancet 358(9291):1421-1423, 2001.

35. McGahon A, Bissonnette R, Schmitt M, et al: BCR-ABL maintains resistanceof chronic myelogenous leukemia cells to apoptotic cell death [published erratumappears in Blood 83(12):3835, 1994]. Blood 83(5):1179-1187, 1994.

36. Bedi A, Barber JP, Bedi GC, et al: BCR-ABL-mediated inhibition ofapoptosis with delay of G2/M transition after DNA damage: A mechanism ofresistance to multiple anticancer agents. Blood 86(3):1148-58, 1995.

37. Jamieson L, Carpenter L, Biden TJ, et al: Protein kinase Ciota activityis necessary for Bcr-Abl-mediated resistance to drug-induced apoptosis. J BiolChem 274(7):3927-30, 1999.

38. Samali A, Gorman AM, Cotter TG: Role of Bcr-Abl kinase in resistance toapoptosis. Adv Pharmacol 41:533-552, 1997.

39. Amarante-Mendes GP, Naekyung KC, Liu L, et al: Bcr-Abl exerts itsantiapoptotic effect against diverse apoptotic stimuli through blockage ofmitochondrial release of cytochrome C and activation of caspase-3. Blood91(5):1700-1705, 1998.

40. Amarante-Mendes GP, McGahon AJ, Nishioka WK, et al: Bcl-2-independentBcr-Abl-mediated resistance to apoptosis: Protection is correlated with upregulation of Bcl-xL. Oncogene 16(11):1383-1390, 1998.

41. Thiesing JT, Ohno-Jones S, Kolibaba KS, et al: Efficacy of STI571, an abltyrosine kinase inhibitor, in conjunction with other antileukemic agents againstbcr-abl-positive cells. Blood 96(9):3195-3199, 2000.

42. Fang G, Kim CN, Perkins CL, et al: CGP57148B (STI-571) inducesdifferentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemiacells to apoptosis due to antileukemic drugs. Blood 96(6):2246-2253, 2000.

43. Gorre ME, Mohammed M, Ellwood K, et al: Clinical resistance to STI-571cancer therapy caused by BCR-ABL gene mutation or amplification. Science293(5531):876-880, 2001.

44. Hochhaus A, Kreil S, Corbin A, et al: Roots of clinical resistance toSTI-571 cancer therapy. Science 293(5538):2163, 2001.

45. Weisberg E, Griffin JD: Mechanism of resistance to the ABL tyrosinekinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood95(11):3498-3505, 2000.

46. Champagne MA, Therrien M, Krailo M, et al: STI571 in the treatment ofchildren with Philadelphia (Ph+) chromosome-positive leukemia: Results from aChildren’s Oncology Group (COG) phase 1 study. Blood 98:137a, 2001.

47. Thomas DA, Cortes J, Giles FJ, et al: Combination of hyper-CVAD withimatinib mesylate (STI571) for Philadelphia (Ph)-positive adult acutelymphoblastic leukemia (ALL) or chronic myelogenous leukemia in lymphoid blastphase (CML-LBP). Blood 98:803A, 2001.

48. Sulzbacher I, Traxler M, Mosberger I, et al: Platelet-derived growthfactor-AA and -alpha receptor expression suggests an autocrine and/or paracrineloop in osteosarcoma. Mod Pathol 13(6):632-637, 2000.

49. Oda Y, Wehrmann B, Radig K, et al: Expression of growth factors and theirreceptors in human osteosarcomas. Immunohistochemical detection of epidermalgrowth factor, platelet-derived growth factor and their receptors: Itscorrelation with proliferating activities and p53 expression. Gen Diagn Pathol141(2):97-103, 1995.

50. Lee SB, Kolquist KA, Nichols K, et al: The EWS-WT1 translocation productinduces PDGFA in desmoplastic small round-cell tumour. Nat Genet 17(3):309-313,1997.

51. Froberg K, Brown RE, Gaylord H, et al: Intra-abdominal desmoplastic smallround-cell tumor: Immunohistochemical evidence for up-regulation of autocrineand paracrine growth factors. Ann Clin Lab Sci 29(1):78-85, 1999.

52. Palman C, Bowen-Pope DF, Brooks JJ: Platelet-derived growth factorreceptor (beta-subunit) immunoreactivity in soft tissue tumors. Lab Invest66(1):108-115, 1992.

53. Gilbertson DG, Duff ME, West JW, et al: Platelet-derived growth factor C(PDGF-C), a novel growth factor that binds to PDGF alpha and beta receptor. JBiol Chem 276(29):27406-27414, 2001.

54. Zwerner JP, May WA: PDGF-C is an EWS/FLI induced transforming growthfactor in Ewing family tumors. Oncogene 20(5):626-633, 2001.

55. Ricotti E, Fagioli F, Garelli E, et al: c-kit is expressed in soft-tissuesarcoma of neuroectodermic origin and its ligand prevents apoptosis ofneoplastic cells. Blood 91(7):2397-2405, 1998.

56. Cohen PS, Chan JP, Lipkunskaya M, et al: Expression of stem cell factorand c-kit in human neuroblastoma. The Children’s Cancer Group. Blood84(10):3465-3472, 1994.

57. Tamborini E, Papini D, Mezzelani A, et al: c-KIT and c-KIT ligand (SCF)in synovial sarcoma (SS): An mRNA expression analysis in 23 cases. Br J Cancer85(3):405-411, 2001.

58. Kilic T, Alberta JA, Zdunek PR, et al: Intracranial inhibition ofplatelet-derived growth factor-mediated glioblastoma cell growth by an orallyactive kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Res 60(18):5143-5150, 2000.

59. Campbell JW, Pollack IF: Growth factors in gliomas: Antisense anddominant negative mutant strategies. J Neurooncol 35(3):275-285, 1997.

60. Simakajornboon N, Szerlip NJ, Gozal E, et al: In vivo PDGF beta receptoractivation in the dorsocaudal brainstem of the rat prevents hypoxia-inducedapoptosis via activation of Akt and BAD. Brain Res 895(1-2):111-118, 2001.

61. Adams J, Palombella VJ, Elliott PJ: Proteasome inhibition: A new strategyin cancer treatment. Invest New Drugs 18(2):109-121, 2000.

62. Adams J, Palombella VJ, Sausville EA, et al: Proteasome inhibitors: Anovel class of potent and effective antitumor agents. Cancer Res59(11):2615-2622, 1999.

63. An WG, Hwang SG, Trepel JB, et al: Protease inhibitor-induced apoptosis:Accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independentmarkers of proteasome inhibition. Leukemia 14(7):1276-1283, 2000.

64. McConkey DJ, Pahler JC, Szanto S, et al: Efficacy and mechanisms ofproteasome inhibitor-induced apoptosis in chronic lymphocytic leukemia. ClinCancer Res 7:3715s, 2001.

65. Hideshima T, Richardson P, Chauhan D, et al: The proteasome inhibitorPS-341 inhibits growth, induces apoptosis, and overcomes drug resistance inhuman multiple myeloma cells. Cancer Res 61(7):3071-3076, 2001.

66. Leblanc R, Catley L, Hideshima T, et al: Proteasome inhibitor PS-341inhibits human multiple myeloma cell growth in a murine model. Blood 98:774a,2001.

67. Sunwoo JB, Chen Z, Dong G, et al: Novel proteasome inhibitor PS-341inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, andangiogenesis in squamous cell carcinoma. Clin Cancer Res 7(5):1419-1428, 2001.

68. Teicher BA, Ara G, Herbst R, et al: The proteasome inhibitor PS-341 incancer therapy. Clin Cancer Res 5(9):2638-2645, 1999.

69. Berenson JR, Ma HM, Vescio R: The role of nuclear factor-kappaB in thebiology and treatment of multiple myeloma. Semin Oncol 28(6):626-633, 2001.

70. Cusack JC Jr, Liu R, Houston M, et al: Enhanced chemosensitivity toCPT-11 with proteasome inhibitor PS-341: Implications for systemic nuclearfactor-kappaB inhibition. Cancer Res 61(9):3535-3540, 2001.

71. Ma MH, Parker KM, Manyak S, et al: Proteasome inhibitor PS-341 markedlyenhances sensitivity of multiple myeloma cells to chemotherapeutic agents andovercomes chemo-resistance through inhibition of the NF-kB pathway. Blood98:473a, 2001.

72. Russo SM, Tepper JE, Baldwin AS, et al: Enhancement of radiosensitivityby proteasome inhibition: Implications for a role of NF-kappaB. Int J RadiatOncol Biol Phys 50(1):183-193, 2001.

73. Elliott PJ, Aghajanian C, Cusack J, et al: Clinical development ofPS-341: From mice to man. Clin Cancer Res 6:4500s, 2000.

74. Harbison MT, Bruns CJ, Bold RJ, et al: Proteasome inhibitor PS-341effective anti-angiogenic agent in the treatment of human pancreatic cancer viathe inhibition of NF-kB and subsequent inhibition of vascular endothelial growthfactor production. Proc Am Assoc Cancer Res 41:71a, 2000.

75. An B, Goldfarb RH, Siman R, et al: Novel dipeptidyl proteasome inhibitorsovercome Bcl-2 protective function and selectively accumulate thecyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, butnot normal, human fibroblasts. Cell Death Differ 5(12):1062-1075, 1998.

76. Kurland JF, Meyn RE: Protease inhibitors restore radiation-inducedapoptosis to Bcl-2-expressing lymphoma cells. Int J Cancer 96(6):327-333, 2001.

77. Aghajanian C, Soignet S, Dizon DS, et al: A phase 1 trial of the novelproteasome inhibitor PS341 in advanced solid tumor malignancies (abstract). ProcAm Soc Clin Oncol 20:85a, 2001.

78. Papandreou C, Pagliaro L, Millikan R, et al: Phase I study of PS-341, anovel proteasome inhibitor, in patients with advanced malignancies (abstract).Proc Am Soc Clin Oncol 19:190a, 2000.

79. Stinchcombe TE, Mitchell BS, Depcik-Smith N, et al: PS-341 is active inmultiple myeloma: Preliminary report of a phase I trial of the proteasomeinhibitor PS-341 in patients with hematologic malignancies (abstract 2219).Blood 96, 2000.

80. Richardson PG, Berenson J, Irwin D, et al: Phase II study of PS-341, anovel proteasome inhibitor, alone or in combination with dexamethasone inpatients with multiple myeloma who have relapsed following front-line therapyand are refractory to their most recent therapy. Blood 98:774a, 2001.

81. Fenteany G, Standaert RF, Reichard GA, et al: A beta-lactone related tolactacystin induces neurite outgrowth in a neuroblastoma cell line and inhibitscell cycle progression in an osteosarcoma cell line. Proc Natl Acad Sci USA91(8):3358-3362, 1994.

82. Soldatenkov VA, Dritschilo A: Apoptosis of Ewing’s sarcoma cells isaccompanied by accumulation of ubiquitinated proteins. Cancer Res57(18):3881-3885, 1997.

83. Orlowski RZ, Eswara JR, Lafond-Walker A, et al: Tumor growth inhibitioninduced in a murine model of human Burkitt’s lymphoma by a proteasomeinhibitor. Cancer Res 58(19):4342-4348, 1998.

84. Kordes U, Krappmann D, Heissmeyer V, et al: Transcription factor NF-kappaBis constitutively activated in acute lymphoblastic leukemia cells. Leukemia14(3):399-402, 2000.

85. Hinz M, Loser P, Mathas S, et al: Constitutive NF-kappaB maintains highexpression of a characteristic gene network, including CD40, CD86, and a set ofantiapoptotic genes in Hodgkin/Reed-Sternberg cells. Blood 97(9):2798-2807,2001.

86. Izban KF, Ergin M, Huang Q, et al: Characterization of NF-kappaBexpression in Hodgkin’s disease: Inhibition of constitutively expressed NF-kappaBresults in spontaneous caspase-independent apoptosis in Hodgkin andReed-Sternberg cells. Mod Pathol 14(4):297-310, 2001.