Inhibidores de Proteasoma

Familia de Inhibidores de Proteasoma

Proteasoma

A partir de la Oncologa Hematolgica

Selected targeted agents effective in hematologic malignancies ( Mieloma Multiple) are being tested in solid tumors
Bortezomib.

Rol Potencial de Bortezomib en Tumores slidos

Single agent Combination with chemotherapy
Lower apoptotic threshold Re-sensitizing (reverse resistance)

Combination with targeted agents

Bortezomib - BCL2 sobreexpresin

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. Bold, UC Davis

Tumores Slidos : Single-Agent

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

Bortezomib en Combinacin con Quimioterapia: Preclnicos Datos

Combination with chemotherapy .
Nawrocki et al. Cancer Res 2005 with cisplatin (pancreas) Chandler et al. J Gastro Surg 2004 with gem (pancreas) Nawrocki et al. Mol Cancer Ther 2004 with docetaxel (pancreas)

Re-sensitizing (reversing resistance) of chemotherapy

Kamat et al. AUA 2003 Gemcitabine refractory transitional cell tumors Papageorgiou et al. Cancer Res 2004 IFN resistant bladder Johnson et al. Oncogene 2003 Overcomes TRAIL resistance (prostate, colon, bladder) Bai et al. Cancer Res 2005 Chemoresistant pancreas

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

G1 Apoptosis

G1

PS-341 induces G1 and G2/M arrest, blocking the M-phase activity of Docetaxel

Docetaxel induces Mphase arrest and apoptosis that is enhanced by PS-341

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.

Proteasome Targets in Lung Cancer

Protein
p27 p53 NFkB Bcl-2, Bcl-xL Bax

Role in Lung Cancer

Tumor suppressor Tumor suppressor; therapy resistance Cell survival; therapy resistance Cell survival; therapy resistance Promote apoptosis

Bortezomib Effects
Stabilization Stabilization Down-regulation Down-regulation Stabilization

Mack, et al. Lung Cancer 2003;41:S89.

Randomized Phase II: Bortezomib vs Docetaxel/Bortezomib

R A N D O M I Z A T I O N
Accrual goal, N = 155

Arm A Bortezomib (n = 75)

Advanced NSCLC Failed first-line Tx firstPS 0-2 0-

Arm B Bortezomib + docetaxel ( n = 80)

Fanucchi, et al. J Clin Oncol 2005; 23(16S): Abs # 7034. Fanucchi et al, ASCO 2004 Abstract 7107

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% 7.8 months 4 months

Fanucchi, et al. J Clin Oncol 2005; 23(16S): Abs # 7034.

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

2 (2%) 22 (19%) 24 (21%) 51 (45%) 75 (66%) 21 (18%) 18 (16%)

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., Oral Presentation ASCO 2006

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

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).

Piperdi et al. (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