特集 Folia Pharmacol. Jpn. 142 P3K/mTOR 新規がん治療薬の研究開発2 要約 P K phosphatidyl inositol -kinase /mtor mammalian target of rapamycin P K Akt mtor mtorc mtorc / P K/mTOR mtorc P K/mTOR 1. はじめに Bcr-Abl kinase multi kinase mutantbraf kinase EML -ALK ALK 塩瀬能伸 Vysis ALK Break Apart FSH Probe Kit cobas BRAF V Mutation Test P K/mTOR 2. がんにおける P3K/mTOR 経路と同時阻害薬の意義 RAS/RAF/MEK/ERK P K/mTOR P K mtor - - - E-mail: shiose.yoshinobu.gn@daiichisankyo.co.jp Title: Current development status and prospect of dual P K/mTOR inhibitors for cancer therapy Author: Yoshinobu Shiose
P K/mTOR P K p p P, P or PP P,, P or PP EGFR GFR P K P K PP PDK Akt Akt PTEN P K PP P K mtor Akt mtorc mtorc mtorc negative feedback P K Akt mtorc Akt S P K/mTOR P K p mtor P K/mTOR p mtorc mtorc mtorc Akt mtorc 3. P3K/mTOR 同時阻害薬の研究開発状況 phase maximum tolerated dose MTD Receptor tyrosine kinase Grb/SOS RS-1 P3K/mTOR pathway MAPK pathway Ras Raf PTEN PDK1 PP2 PP3 AKT p85 P3K p110 mtor-rictor (mtorc2) P3K/mTOR 同時阻害薬 mtor-raptor (mtorc1) MEK MDM2 4E-BP1 S6K ERK GSK3 FOXO p53 ef4e S6 Cell proliferation differentiation Metabolism Control of apoptosis Cell survival Protein synthesis Cell growth 図 1 P3K/mTOR 経路と細胞機能への関わり 表 1 Pl3K/mTOR 経路を活性化する遺伝子変異 P K/mTOR PK CA p mutation PK CA p amplification PK R p mutation AKT mutation AKT amplification PTEN mutation
FDG-PET Phase phase Phase phase P K/mTOR phase P K/mTOR BEZ Novartis GDC - Genentech XL - /SAR Exelixis/Sanofi PF- /PK- Pfizer PF -Pfizer GSK - G l a x o S m i t h K l i n e P W T P a t h w a y Therapeutics DS- BEZ- P K/mTOR LY wartmanin P K BEZ ASCO phase Gelatin capsule qd, mg partial response PR germline PTEN mutation Cowden syndrome Her minor response MR stable disease SD P K F-FDG mg bid phase / GDC - phase qd mg mg F-FDG mg Grade Gr MTD phase mg XL- phase bid qd cycle bid mg qd mg bid qd MTD mg mg AST/ALT Gr AST/ALT bid mg mg Qd bid XL- Median T max h h PF- phase mg P K/mTOR MTD mg h Gr EGFR PR SD PF- phase qd mg MTD mg h Gr Her SD GSK phase qd. mg MTD. mg T max h h DLT Gr. mg / mg / G / G / G /. mg
P K/mTOR mg PR PWTDS- phase 4. P3K/mTOR 同時阻害薬の併用療法 National nstitutes of Health ClinicalTrials.gov b BEZ GDC - XL - BEZ Her P K PK CA P K/mTOR MEK MEK pan-p K BKM mtorc University of Cincinnati BEZ Her GDC - Her P K/mTOR GDC- mtorc GDC- pan -P K GDC- XL- pan -P K XL- MEK MSC B BEZ GDC- P K/mTOR XL- PF- PF - P K/mTOR P K/ mtor P K pan-p K RAF/MEK/ ERK MEK P K/mTOR MEK Akt mtor 5. P3K/mTOR 同時阻害薬のバイオマーカー predictive pharmacodynamic PD BEZ GDC- XL- phase
表 2 P3K/mTOR 同時阻害薬の臨床試験 Compound Company BEZ Novartis GDC- Genentech XL- Sanofi PF- PF- Pfizer GSK- Glaxo Smith Kline Study A Multicenter Phase / Trial of Abiraterone Acetate BEZ in Metastatic Castration-Resistant Prostate Cancer A Phase / Study of BEZ in Patients With Advanced Solid Malignancies Enriched by Patients With Advanced Breast Cancer Clinical phase / / ClinicalTrials.gov dentifier NCT NCT BEZ in Patients With Advanced Renal Cell Carcinoma RCC / NCT Dose Finding Study of RAD Everolimus Afinitor in Combination With BEZ in Patients With Advanced Solid Tumors A Phase b/ Study of BEZ and Trastuzumab in Patients With HER -positive Breast Cancer Who Failed Prior to Trastuzumab b/ NCT NCT A Trial of Oral BEZ and BKM in Combination With Paclitaxel With or Without Trastuzumab NCT A Phase, Dose-finding Study of BEZ in Adult Patients With Relapsed or Refractory Acute Leukemia NCT Study of BKM or BEZ and Capecitabine in Patients With Metastatic Breast Cancer NCT Safety Pharmacokinetics and Pharmacodynamics of BEZ Plus MEK in Selected Advanced Solid Tumor Patients A Phase Study of Orally Administered BEZ Monotherapy in Patients With Metastatic or Unresectable Malignant PEComa Efficacy and Safety of BEZ Compared to Everolimus in Patients With Advanced Pancreatic Neuroendocrine Tumors MACS Phase b/ Trial of BEZ With Paclitaxel in Patients With HER Negative Locally Advanced or Metastatic Breast Cancer b/ NCT NCT NCT NCT Safety Study of BEZ With Everolimus in Subjects With Advanced Solid Tumors b/ NCT Phb BKM or BEZ Endocrine Treatment in Post-Menopausal Patients With Hormone Receptor Metastatic Breast Cancer BEZ Phase Trial in Patients With Advanced Pancreatic Neuroendocrine Tumors pnet After Failure of mtor nhibitor Therapy A Study Evaluating GDC- Administered Once Weekly in Patients With Refractory Solid Tumors or Non-Hodgkin s Lymphoma A Study Evaluating GDC- Administered Once Daily in Patients With Refractory Solid Tumors or Non-Hodgkin s Lymphoma b NCT NCT NCT NCT A Study of GDC- in the Treatment of Recurrent or Persistent Endometrial Carcinoma NCT Study of GDC- or GDC - With Fulvestrant Versus Fulvestrant in Advanced or Metastatic Breast Cancer in Patients Resistant to Aromatase nhibitor Therapy Study of the Safety and Pharmacology of GDC- in Combination With Paclitaxel With or Without Bevacizumab in Patients With Locally Recurrent or Metastatic Breast Cancer GDC- in Combination With a Fluoropyrimidine Oxaliplatin and Bevacizumab in Patients With Advanced Solid Tumors A Study of the Safety and Pharmacology of GDC- in Combination With Either Paclitaxel and Carboplatin With or Without Bevacizumab or Pemetrexed and Cisplatin in Patients With Solid Tumors Study of GDC- Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma Who Have Progressed on or Following Vascular Endothelial Growth Factor- VEGF Targeted Therapy Exploratory Study of XL SAR or XL SAR in Subjects With Recurrent Glioblastoma Who Are Candidates for Surgical Resection Study of XL SAR or XL SAR in Combination With Letrozole in Subjects With Breast Cancer / NCT NCT NCT NCT NCT NCT NCT Safety Study of XL SAR in Combination With Erlotinib in Adults With Solid Tumors NCT Trial of MEK nhibitor and P K/mTOR nhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors A Study of XL SAR in Combination With Temozolomide With and Without Radiation in Adults With Malignant Gliomas Study Of P K/mTOR nhibitors n Combination With A MEK nhibitor Or rinotecan n Patients With Advanced Cancer A Study Of Two Dual P K/mTOR nhibitors, PF- And PF- n Patients With Recurrent Endometrial Cancer Study to nvestigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK and GSK Combination Therapy in Subjects With Advanced Solid Tumors b NCT NCT NCT NCT NCT BEZ XL - P K/mTOR GDC- Akt
P K/mTOR 表 3 P3K/mTOR 同時阻害薬の臨床試験時のバイオマーカー (14) Drug Acquired PD biomarker Skin Hair PBMC/plasma Tumor FDG-PET BEZ Comments/findings dose-dependent in plasma C -peptide ps, Ki in tumor biopsies selected cases in FDG-PET uptake in of pts GDC- pakt in platelet rich plasma XL- Modest in plasma insulin P K pathway inhibition in hair & skin across doses including MTD Robust P K pathway inhibition across diverse tumor types: pakt S pakt T p EBP MAPK pathway inhibition in tumors: perk PD P K/mTOR c-peptide P K/mTOR PD FDG-PET F-FDG predictive PK CA PTEN ERBB P K/mTOR predictive pan -P K Akt mtor mtorc 謝辞 著者の利益相反 : 文 Engelman JA. Nature Rev. ; :-. O Reilly KE, et al. Cancer Res. ; : -. Garcia-Echeverria C, et al. Oncogene. ; : -. Figlin RA, et al. nt J Cancer. Jan. doi:. /ijc.. Burris H, et al. J Clin Oncol. ; Suppl:abstr. Wagner AJ, et al. J Clin Oncol. ; Suppl:abstr. Brana, et al. J Clin Oncol. ; Suppl:abstr. Tabernero J, et al. Mol Cancer Ther. ; Suppl:A. LoRusso PM, et al. Mol Cancer Ther. ; Suppl:B. Munster PN, et al. J Clin Oncol. ; Suppl:abstr. Andrea LA, et al. nt J Breast Cancer.. doi:. / /. Schatz JH. Curr Oncol Rep. ; :-. Shimizu T, et al. Clin Cancer Res. ; : -. Markman B, et al. Oncotarget. ; :-. Weigelt B, et al. Front Oncol. ; : -. 献 6. おわりに P K/mTOR P K/mTOR