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Published by: Hong Wu on Feb 22, 2012
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Inhibidores de Proteasoma

Familia de Inhibidores de Proteasoma .

Proteasoma .

A partir de la Oncología Hematológica ‡ Selected targeted agents effective in hematologic malignancies ( Mieloma Multiple) are being tested in solid tumors ± Bortezomib. .

Rol Potencial de Bortezomib en Tumores sólidos Single agent Combination with chemotherapy Lower apoptotic threshold Re-sensitizing (reverse resistance) Combination with targeted agents .

Bold.BCL2 sobreexpresión Control Gemcitabine Paclitaxel (10 M) (10 M) PS-341 (10 M) Control Gemcitabine Paclitaxel (10 M) (10 M) PS-341 (10 M) Courtesy of R. UC Davis .Bortezomib .

pancreas ‡ Respuesta de alrededor de 5%.Pobre . esophageal. CRC. melanoma. 1 PR (leiomyosarcoma) ‡ Phase II ± no responses: breast.Tumores Sólidos : Single-Agent ‡ Phase I ± solid tumor studies: responses in HRPC. 1 PR ‡ Phase II ± sarcomas 21 pts. 1 CR (medullary). SCCHN (NP) ‡ Phase II ± advanced transitional cell cancer of the bladder/renal pelvis/ureter: No responses ‡ Phase II ± metastatic neuroendocrine tumors (carcinoid. ovary. 3 PR ‡ Phase II ± recurrent SCLC (SWOG) 56 pts. islet cell) No responses ‡ Phase II ± chemona ve adv RCC 21 pts 1 PR ‡ Phase II ± adv RCC 37 pts. hepatocellular. NSCLC.

Cancer Res 2005 with cisplatin (pancreas) Chandler et al. Cancer Res 2004 IFN resistant bladder ± Johnson et al. colon. Cancer Res 2005 Chemoresistant pancreas .Bortezomib en Combinación con Quimioterapia: Preclínicos Datos Combination with chemotherapy . Oncogene 2003 Overcomes TRAIL resistance (prostate. Nawrocki et al. AUA 2003 Gemcitabine refractory transitional cell tumors ± Papageorgiou et al. J Gastro Surg 2004 with gem (pancreas) Nawrocki et al. bladder) ± Bai et al. Mol Cancer Ther 2004 with docetaxel (pancreas) Re-sensitizing (reversing resistance) of chemotherapy Kamat et al.

blocking the M-phase activity of Docetaxel Docetaxel induces Mphase arrest and apoptosis that is enhanced by PS-341 .Efectos de la secuencia de PS-341 + Docetaxel Un modelo de respuesta PS-341 p Docetaxel Docetaxel p PS-341 Apoptosis Apoptosis M G2 Cell Cycle M G2 Cell Cycle S G1 Apoptosis S G1 PS-341 induces G1 and G2/M arrest.

Schedule importance: Bortezomib with gemcitabine/carboplatin Control Bort alone Bort->Chemo Long-Term Cell Viability Assay A549 NSCLC Chemo only Chemo->Bort Concurrent Mortenson et al. Cancer. Chem & Pharm 2004. .

. et al. therapy resistance Cell survival. therapy resistance Promote apoptosis Bortezomib Effects Stabilization Stabilization Down-regulation Down-regulation Stabilization Mack.Proteasome Targets in Lung Cancer Protein p27 p53 NFkB Bcl-2. therapy resistance Cell survival.41:S89. Lung Cancer 2003. Bcl-xL Bax Role in Lung Cancer Tumor suppressor Tumor suppressor.

N = 155 Arm A Bortezomib (n = 75) Advanced NSCLC Failed first-line Tx firstPS 0-2 0- Arm B Bortezomib + docetaxel ( n = 80) Fanucchi. ASCO 2004 Abstract 7107 . J Clin Oncol 2005. et al. 23(16S): Abs # 7034. Fanucchi et al.Randomized Phase II: Bortezomib vs Docetaxel/Bortezomib R A N D O M I Z A T I O N Accrual goal.

J Clin Oncol 2005.Randomized Phase II: Results Bortezomib N RR SD Median survival Median TTP 75 8% 21% 7.4 months 1.5 months Bortezomib + Docetaxel 80 9% 45% 7. et al. . 23(16S): Abs # 7034.8 months 4 months Fanucchi.

Oral Presentation ASCO 2006 2 (2%) 22 (19%) 24 (21%) 51 (45%) 75 (66%) 21 (18%) 18 (16%) .S0339: Response Rate (RECIST) N = 114 Complete Response Partial Response ORR (CR+PR) Stable Disease Disease Control Rate (ORR+SD) Progressive Disease Inadequate/Unknown Davies et al..

Oral Presentation ASCO 2006 .Adversos ‡ Most common adverse events (• grade 3) ± Neutropenia: 52% ± Thrombocytopenia: 63% ± Anemia: 13% ± Fatigue: 13% ‡ Low rate of grade 3/4 neuropathy (5%) likely due to low bortezomib dose ‡ Grade 5 toxicity: 4 deaths possibly related to treatment Davies et al..

Ongoing Phase II Trials Tumor Type Head and Neck Colorectal Glioma Hepatocellular Melanoma Nasopharyngeal Gastroesophageal Kidney Thyroid Bile Duct/Gallbladder Cervical/Vulvar/Vaginal Renal Regimen Bortezomib + Irinotecan Bortezomib + Irinotecan Bortezomib + Tamoxifen Bortezomib + Doxorubicin Bortezomib + Paclitaxel + Carboplatin Bortezomib + Gemcitabine Bortezomib + Irinotecan Bortezomib Bortezomib Bortezomib Bortezomib + Irinotecan Bortezomib + Bevacizumab .

Combination of Bortezomib With Other Targeted Agents .

. ‡ Piperdi et al.Bortezomib and Erlotinib ‡ Hypothesis: erlotinib + bortezomib may synergistically affect EGFR pathway ± Erlotinib blocks EGFR-TKI ± Bortezomib increasing degradation of activated EGFR and its ligand. the epidermal growth factor (EGF). (AACR 2005) preclinical NSCLC models ± Bortezomib + erlotinib more effective than either alone in erlotinib-sensitive H358 bronchioloalveolar cells.

Bortezomib in Solid Tumors: Conclusions Bortezomib more likely to be of benefit in combination with chemotherapy by lowering apoptotic threshold Bortezomib + chemotherapy has yielded promising results in NSCLC Optimal sequencing of bortezomib + chemotherapy question for clinical trials Bortezomib + targeted agents warrants clinical evaluation .

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