PI3K抑制剂Buparlisib (BKM120)的相关信息

这个药在乳腺癌中也有不少进入了三期试验，看来还是很有前途的

A phase Ib safety and tolerability study of a pan class I PI3K inhibitor buparlisib
(BKM120) and gefitinib (gef) in EGFR TKI-resistant NSCLC.
Daniel Shao-Weng Tan, Kiat Hon Lim, Wai Meng Tai, Aziah Ahmad, Summer Pan, Quan Sing Ng,
Mei-Kim Ang, Apoorva Gogna, Yuen Li Ng, Bien Soo Tan, Haur Yueh Lee, Sakktee Sai Krisna,
Dawn PX Lau, Liz Zhong, Gopal Iyer, Balram Chowbay, Alvin ST Lim, Angela Takano, Wan-Teck Lim,
Eng-Huat Tan; National Cancer Centre, Singapore, Singapore; Department of Pathology, Singapore
General Hospital, Singapore, Singapore; Singhealth Investigational Medicine Unit, Singapore, Singapore;
Department of Radiology, Singapore General Hospital, Singapore, Singapore; Department of Dermatology,
Singapore General Hospital, Singapore, Singapore; Cytogenetics Laboratory, Singapore General Hospital,
Singapore, Singapore
Background: Overcoming EGFR TKI resistance (R) is a major clinical challenge; reported mechanisms
include EGFR T790M mutation (mt), MET amplification (amp) and PIK3CA mt. As the PI3K pathway is
a central convergent signaling node, we hypothesized that addition of buparlisib (BKM) could overcome
EGFR TKI-R. Methods: Patients (pt) resistant to EGFR TKI (Jackman JCO 2010) were enrolled to
determine safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of BKM-gef. Using a “313”
design, escalating doses of BKM were added to pt progressing on gef (Gp A). Pt not on gef preceding
enrolment received a 2 wk run in (Gp B). Given the favorable CNS penetration of BKM, a CNS gp with
brain metastases only was included. Pt had pretreatment biopsies and sequential PET-CT scans (baseline &
d28). Results: 15 pt have been treated at 3 dose levels: BKM 80 mg/d (n56), 100 mg/d (n56), 80 mg 5d
on 2d off (5/2, n53), with gef 250 mg/d. Gp A (n59, 1 CNS), B (n56, 1 CNS), F:M (9:6), median age 63
(47-73) and majority .3 lines of therapy. DLT was G3 diarrhea observed in 2/6 pt at BKM100. Common
adverse events (AE, all grades) include rash (80%), diarrhea (73%), fatigue (60%), anorexia (47%),
mucositis (40%). Notably, 40% of pt had late (beyond DLT period) G3 toxicities such as rash and diarrhea.
MTD is BKM 80/d and gef 250/d. To improve the overall safety profile, an intermittent schedule of BKM80
5/2 was also found to be feasible. In gp B, PET-CT done after 2 wk run-in of gef, 3/4 evaluable pt
demonstrated reduction in SUVmax of which 1 had PR. With addition of BKM, reduction in SUVmax
(.25%) was seen in 4/10 pt (gp A & B). Median PFS 2.8 m (95%CI 2.3 – 8.1), two pt in CNS gp had PFS
of 2.8 and 10.7 m. Molecular analyses revealed 6/12 (50%) harbored T790M mt, 2/5 (40%) MET amp, 0/12
PI3KCA mt. In gp A, 4/9 pt (2 T790M; 1MET amp) had clinical responses, including slight tumor shrinkage
and reduced pleural effusion, but required dose reductions due to AE. PK profiles are being analyzed.
Conclusions: MTD is gef 250-BKM 80/d. Antitumor activity has been observed with addition of BKM in
EGFR TKI-R pt. In view of late toxicities and long t½ of BKM, exploring alternative schedules is warranted.
A dose expansion cohort at MTD is currently ongoing. Clinical trial information: NCT01570296.

祝福入组的人能取得好的治疗效果。

每天都有许多让人盼望的好消息，尽管看得不是很明白，但期待大家的好疗效，为了我们的亲人争取更多的时间！在这里感谢论坛里默默付出的这群人，你们的大爱感天动地，更令群里的无数病友感动，祝好人好运！

PI3K抑制剂Buparlisib(BKM120)和吉非替尼在非小细胞肺癌EGFR突变TKI耐药治疗中的安全和耐受性的IB阶段研究

背景:
克服吉非替尼耐药是现在重要的临床挑战, 现在所知道的耐药的原因包括EGFR T790M突变, MET扩增, 以及PI3K突变. 因为PI3K是中央的信号汇聚节点. 所以我们在这里假设联用 BKM120能克服EGFR耐药.
方法:
对吉非替尼耐药的病人参加了实验小组，来研究BKM-gef的安全性，耐受性，药代动力学性和药效。使用313用药模式，对于服用吉非替尼进展的病人逐步升级BKM的剂量(A组)。B组为服用吉非替尼而没有进展的病人,用药两周。为了测试对大脑的渗入能力，俩组各有一个脑转病人加入。病人在加入小组前都做了活检和PetCT。
小组结果:
15个病人服用了３个剂量的药, BKM 80 mg/d (6人), 100 mg/d (6人), 80 mg吃５天，停２天。同时每天服用250mg吉非替尼。A组(9人, 其中1名脑转病人), B组(6人, 其中1名脑转病人), 男女比例9:6,中位年纪63岁 (47-73岁),大部分为３线治疗。剂量限制毒性包括33.3%的病人在服用BKM120 100mg发生3级腹泻。常见的不良反应（所有剂量组）包括皮疹(80%)，腹泻(73%)，疲劳(60%)，厌食(47%)，黏膜炎(40%)。值得注意的是，40%的病人有延迟性3级毒性，例如皮疹，腹泻。
最大的服用计量为BKM120 80mg/d | 吉非替尼250mg/d, 为了提高服用安全性, 间歇服用BKM120 80mg(服药5天停药2天)也是可行的.
B组, 4名病人服药2周后, PET-CT显示,3名病人SUVmax值降低,包括一位脑转病人。12个病人的活检结果显示50%的病人有T790M突变，40%的病人有MET扩增，没有病人有PI3K突变。A组，4名（44.4%）病人（2个T790M突变，1个MET扩增）有临床反应，包括轻微的肿瘤缩小和胸腔积液的减少，但是因为不良反应，不得不减少用药剂量。A组和B组通过服用加量的BKM120，40%的病人发现SUVmax下降25%，中位无进展时间为2.8月，两位脑转的病人的中位无进展时间分别为2.8月和10.7月。药代动力学还在分析中。
结论：
联合用药的最大耐受剂量是吉非替尼250mg + BKM120 80mg每天。联合BKM120对已经产生吉非替尼耐药的病人起了抗肿瘤作用。对于BKM120的后期和持续性的毒副作用，另外的用药方案应被研究。最大耐受剂量组的临床试验正在进行中。临床试验组号为NCT01570296。

这是4月份时代周刊杂志，发表“如何治愈癌症”文章里，其中一段关于PI3K的描述，都是重量级人士在研究这个PI3K，但他们更多是着重于女性（ovarian, endometrial and especially breast）的试验，仅供参考！

Cancer is a thief and biological con artist, breaking into and taking control of the mechanisms of a cell and coaxing it to grow and divide in dangerous ways. Cantley has spent a career chasing this cellular saboteur by, as he describes it, “teasing out signaling pathways” that govern not just growth but the very life span of a cell. If the malignant signaling can be silenced or reversed, the cancer won’t spread. In pursuit of that, he is now a co-leader of a team backed by SU2C that targets a pathway called PI3K, short for phosphoinositide 3-kinase. The pathway is a known driver in three women’s cancers: ovarian, endometrial and especially breast, which involves the PI3K mutation in 30% of cases. Says Cantley: “It’s the most frequently mutated oncogene in cancer.”
Drug companies have long been targeting mutations like this one to develop compounds that will interfere with the defective biochemical gateways. There are hundreds of drugs that may have some effect against some of the mutations, which sounds like an abundance of riches — but it’s also an abundance of complexity. That’s one reason that the pharma industry has a 95% failure rate for new products and that half of Phase III trials — the last step before approval — don’t cut it. “If I have 100 different drugs I can use in combination, then 100 times 100 is 10,000. You can’t do 10,000 trials,” says Sharp. But which ones can you do and should you do and on which patients? Since PI3K mutations are the most common type, those seemed like a perfect place to start for Cantley’s dream team, which is co-led by Dr. Gordon Mills of MD Anderson — another world-class PI3K pathway investigator — along with women’s-cancer specialists from Massachusetts General, Dana Farber (Harvard), Vanderbilt, Columbia University, Beth Israel Deaconess and Memorial Sloan-Kettering.
The goal is to launch trials as rapidly as the geneticists and biochemists solve the equation of matching mutations with drug compounds. In one of the best examples of the new model, Cantley, Dr. Gerburg Wulf and another researcher, José Baselga, proposed combining a PI3K inhibitor with a PARP inhibitor to combat a particularly pernicious mutation in the BRCA1 gene that results in high risk for developing ovarian cancer and a severe type of breast cancer known as triple-negative. PARP is the abbreviation for a group of enzymes that do repair work on damaged DNA strands — usually a good thing, unless the strands are producing cancer cells. Working on mouse models, the team got cures for BRCA1 mutant and triple-negative breast cancers when they combined a PI3K inhibitor and PARP inhibitor, which had never happened with other therapies.
Moving on to a human trial was also easier than it ordinarily is and illustrates what the new paradigm means for Big Pharma. The team needed a PI3K inhibitor from Novartis and a PARP inhibitor from AstraZeneca. Neither drug is approved for cancer treatment, and it’s rare to conduct a trial in which two unapproved drugs are combined. Because of concerns about intellectual property and other issues — no drugmaker wants to be smeared by the toxicity of another’s drug — companies are wary of collaboration. The success of the Cantley-Mills team had drug firms lining up. “Every company that had a PI3K inhibitor called me and asked would I work with them,” says Cantley. The result was almost without precedent: a human trial at five institutions with two unapproved drugs from two companies within about a year of discovery. “Four years ago if you said you were going to do that, you would have been laughed out of the room.”

Asco 2013
2015-Essai de phase II de BKM120, inhibiteur de la phosphatidyinositol-3 kinase (PI3K) pour glioblastome récurrent. P.Y. Wen
Auteurs : Patrick Y. Wen, W. K. Alfred Yung, Ingo K. Mellinghoff, Kathleen Lamborn, Shakti Ramkissoon, Timothy Francis Cloughesy, Mikael Rinne, Antonio Marcilio Padula Omuro, Lisa Marie DeAngelis, Mark R. Gilbert, Andrew S. Chi, Tracy Batchelor, Howard Colman, Susan Marina Chang, Cristian Massacesi, Emmanuelle DiTomaso, Michael Prados, David A. Reardon, Keith L. Ligon; Dana-Farber Cancer Institute, Boston, MA; The University of Texas MD Anderson Cancer Center, Houston, TX; Memorial Sloan-Kettering Cancer Center, New York, NY; University of California, San Francisco, San Francisco, CA; David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA; Dana-Farber Cancer institute, Boston, MA; Massachusetts General Hospital, Boston, MA; University of Utah, Huntsman Cancer Institute, Salt Lake City, UT; Novartis Pharma SAS, Rueil-Malmaison, France; Novartis Institutes for BioMedical Research, Inc., Cambridge, MA; Dana-Farber Cancer Institute/Brigham and Women's Hospital/ Boston Children's Hospital, Boston, MA
L'article original :
Résumé :
La voie PI3K est activée dans la plupart des GBMs et représente une cible thérapeutique potentielle. BKM120 est inhibiteur oral de PI3K qui pénètre dans le cerveau à des concentrations thérapeutiques suffisantes pour inhiber la voie PI3K, et peut inhiber in vitro la croissance des tumeurs U87 tumeurs et les sphères de gliomes humains in vivo.
Méthodes :
Cet essai de phase II étudie BKM120 chez les malades avec GBM récurrent avec activation de la voie PI3K (mutation, suppression homozygote ou perte d'IHC de PTEN, PIK3CA ou mutations PIK3RI, ou pAKT détectable). Les critères d'éligibilité supplémentaires ont inclus la progression de l'IRM, 1ère ou 2ème rechute, > 18 ans, KPS> 60, moelle épinière adéquate et fonction de l'organe, glucose du sang contrôlée, et aucun traitement anti-épileptique enzyme-induisant. Les malades ont reçu BKM120 100mg quotidiennement. L'étude s'est faite en 2 parties menées concurremment. La 1ère partie, jusqu'à 15 malades ont reçu BKM120 journalier pour 8-12 jours avant la chirurgie pour maladie récurrente. Les malades ont alors subi Pet Scan FDG PET, pharmacokinetic (PK) études, et la tumeur a été obtenue pour les concentrations de médicament et les effets pharmacodynamiques. La 2ème partie a concerné 50 malades avec GBM non résécable traités avec BKM120. Le, point final fondamental pour la 2ème partie était la survie sans progression à 6 mois.
Résultats :
A ce jour 7 malades ont été inscrits en 1ère partie et 33 en 2ème partie. Sur ces 40, 5 femmes et 35 hommes. L'âge médian était de 54 ans (29-68 ans). Le traitement a été bien toléré. Des niveaux 3/4 de toxicités étaient l'élévation de lipase asymptomatique (5), la fatigue (3), l'hyperglycémie (3), irréfléchi (3) AST élevé (1), et dépression (1). L'analyse de tumeur en 1ère partie a montré une réduction de pAkt par IHC. Le génotypage des spécimens de tumeur est progressif. Sur les 33 malades avec pAkt positif, 21 pertes PTEN par IHC. Les premiers 19 malades qui ont subi des séquençages d'exomes, 3 mutations PIK3Ca et 6 mutations PTEN.
Conclusions :
BKM120 est bien toléré généralement chez les malades avec GBM récurrent. les concentrations de BKM120 dans la tumeur sont adéquates pour inhiber pAkt. Les données mises à jour et des données d'efficacité en corrélation avec le génotype de la tumeur sera présenté à la réunion. Information du procès clinique: NCT01339052.

又多了一个希望。

Treatment Targeting PI3K May Delay Resistance to Anti-HER2 Therapy in Breast Cancer Patients
http://www.aacr.org/home/public- ... he-news.aspx?d=3015
PHILADELPHIA — Patients with HER2-positive breast cancer being treated with anti-HER2 therapy may be able to prevent or delay resistance to the therapy with the addition of a phosphatidylinositol-3 kinase inhibitor to their treatment regimens.

The data, published in Cancer Research, a journal of the American Association for Cancer Research, indicated that failure of the anti-HER2 antibody trastuzumab to block HER2 from activating the phosphatidylinositol-3 kinase (PI3K) signaling pathway can lead to resistance to treatment. Therefore, dual simultaneous inhibition of both HER2 and PI3K may prolong the use of anti-HER2 therapies in women with breast cancer.

“HER2 breast cancer is a subtype of breast cancer for which we have an increasing number of effective treatments, including trastuzumab, an antibody that targets HER2,” said Carlos L. Arteaga, M.D., director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn. “Unfortunately, many breast cancer tumors learn how to resist this therapy.”

Arteaga and colleagues explored the possibility that aberrant signaling through the PI3K pathway was a mechanism of resistance to trastuzumab. They used breast cancer models of trastuzumab resistance with different modes of aberrant PI3K pathway activation, and treated the cells with a PI3K inhibitor with or without trastuzumab.

Inhibiting PI3K reduced cancer cells’ ability to proliferate and induced the death of trastuzumab-resistant cells. In addition, combining PI3K inhibitors with trastuzumab resulted in superior anti-tumor effects against trastuzumab-resistant, HER2-positive cells in xenografts compared with the PI3K inhibitor alone.

The investigators also conducted analyses to determine how the drug combination decreased resistance to trastuzumab.

“We found that the trastuzumab-resistant cells in which the PI3K pathway was activated had high levels of an anti-death protein called survivin,” Arteaga said. “This implied that if we could get levels of survivin to decrease, these cells would become sensitive to treatment.”

They also measured pretreatment levels of survivin in HER2-positive breast cancer tumors and found that higher pretreatment levels of the protein correlated with a poor response to therapy.

“This suggests that we could measure levels of survivin in tumors, and if they are high or do not decrease with treatment, we could predict that the tumor is resistant to anti-HER2 therapy and try to find alternative treatments,” Arteaga said.

Arteaga and colleagues plan to continue testing PI3K inhibitors, which are already in early clinical development, in combination with other HER2 drugs in breast cancer. They also plan to measure survivin levels in HER2-overexpressing breast cancer tumors to determine if levels can predict tumors that will benefit from combination treatment.

http://www.ncbi.nlm.nih.gov/pubmed/21220474
Clin Cancer Res. 2011 Apr 15;17(8):2260-9. doi: 10.1158/1078-0432.CCR-10-1993. Epub 2011 Jan 10.
Transient PI3K inhibition induces apoptosis and overcomes HGF-mediated resistance to EGFR-TKIs in EGFR mutant lung cancer.
Donev IS, Wang W, Yamada T, Li Q, Takeuchi S, Matsumoto K, Yamori T, Nishioka Y, Sone S, Yano S.
SourceDivision of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

Abstract
PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, show favorable response to EGFR mutant lung cancer. However, the responders acquire resistance almost without exception. We recently reported that hepatocyte growth factor (HGF) induces EGFR-TKI resistance by activating MET that restores downstream mitogen activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)1/2 and phosphoinositide 3-kinase (PI3K)/Akt signaling. The purpose of this study was to determine whether inhibition of PI3K, a downstream molecule of both EGFR and MET, could overcome HGF-mediated EGFR-TKI resistance in EGFR mutant lung cancer cells PC-9 and HCC827.

EXPERIMENTAL DESIGN: We explored therapeutic effect of a class I PI3K inhibitor PI-103 on HGF-induced EGFR-TKI resistance in vitro and in vivo.

RESULTS: Unlike gefitinib or erlotinib, continuous exposure with PI-103 inhibited proliferation of PC-9 and HCC827 cells, even in the presence of HGF. On the other hand, in gefitinib-resistant xenograft model by using PC-9 cells mixed with HGF high producing fibroblasts, PI-103 monotherapy did not inhibit tumor growth. However, PI-103 combined with gefitinib successfully regressed gefitinib-resistant tumor. In vitro experiments by considering short half-life of PI-103 reveal that transient exposure of PI-103 combined with gefitinib caused sustained inhibition of Akt phosphorylation, but not ERK1/2 phosphorylation, resulting in induction of tumor cell apoptosis even in the presence of HGF.

CONCLUSIONS: These results indicate that transient blockade of PI3K/Akt pathway by PI-103 and gefitinib could overcome HGF-mediated resistance to EGFR-TKIs by inducing apoptosis in EGFR mutant lung cancer.