【drug-news】对用于非小细胞肺癌治疗的PKC抑制剂未来发展的思考（征集全文翻译，加分从优！）===置顶第30贴

PKC抑制剂为肿瘤领域研究热点，该文段作者阐述了PKC抑制剂在肿瘤领域尤其是NSCLC治疗中的研究进展，文中提供了目前为止全世界该类药物最新的临床研究成果。
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CONSIDERATIONS FOR THE FUTURE DEVELOPMENT OF PKC INHIBITORS IN NSCLC
对用于非小细胞肺癌治疗的PKC抑制剂未来发展的思考

1.
Despite modest improvements in treatment-related toxicities, the efficacy of first- and second-line chemotherapy treatment for metastatic NSCLC has not changed appreciably during the last decade . Equally important is the fact that many patients will not benefit from the current chemotherapies (i.e., the response rate is generally between 20% and 30% at best), and other patients will not be eligible to receive chemotherapy due to their co-morbidities or other ineligibility reasons (performance status, etc.). Therefore, some of the most significant therapeutic advances for metastatic NSCLC during the last several years have focused on developing agents that are more selective in their antitumor effect with the hope of reducing toxicities. One approach was directed at targeting the EGFR and VEGFR pathways . As a result of this effort, the addition of bevacizumab, a monoclonal antibody against VEGF, to standard front-line chemotherapy with carboplatin and paclitaxel for NSCLC has been shown to improve response rates, time to progression, and overall survival compared to chemotherapy alone. Based on these results, the U.S. Food and Drug Administration has approved bevacizumab for use in combination with chemotherapy to treat meta- static NSCLC. In contrast to first-line therapy, standard second-line therapy for metastatic NSCLC has been limited to several single-agent chemotherapy drugs, all associated with a similar 10% to 15% rate of tumor response and overall survival. This situation changed with the arrival of molecular targeted agents; in particular, EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib . These agents have shown a marked benefit for appropriately selected patients with metastatic NSCLC. This recent experience of bevacizumab and the tyrosine kinase inhibitors suggests that inhibition of pathways associated with tumor proliferation or angiogensis can alter the clinical outcome of patients with NSCLC. It is understandable that many other VEGFR and EGFR pathway antagonists are currently being evaluated with great interest, either separately or in combination for the treatment of NSCLC .
2.
The success of the EGFR and VEGFR pathway antagonists in treatment of metastatic NSCLC has important implications for development of novel targeted therapies such as the PKC inhibitors. The development of EGFR and VEGFR pathway antagonists has been blessed by a clear appreciation of the biology targeted by these therapeutic agents. Bevacizumab, gefitinib, and erlotinib by design have exquisitely well-defined molecular targets that facilitate rigorous testing of their mechanisms of action and pharmacodynamics. Fortuitously, these drugs also have clinically obvious pharmacodynamic end points—hypertension for bevacizumab and skin toxicity for erlotinib and gefitinib. Even despite these clear molecular, biologic, and clinical endpoints of therapy, the results of clinical trials with these agents still have been marked by unexpected results and discoveries that have reinvented their therapeutic indications.
3.
It appears that PKC inhibitors act on similar and, in some instances, distinct pathways compared to those of the EGFR and VEGFR inhibitors. Hence, it is not unlikely that they will also provide clinical benefit in the treatment of lung cancer. PKC inhibitors can inhibit cell cycle , tumor cell proliferation, and neo-angio- gensis, and can induce apoptosis . This multivalent activity of PKC inhibitors is based on a broader antitumor biology than the EGFR and VEGFR inhibitors. In contrast to the approved VEGFR and EGFR inhibitors, PKC inhibitors are only at the beginning of their discovery path, and their development path will likely be as challenging as the one for the VEGFR and EGFR inhibitors. Several aspects need to be considered for the successful clinical development of PKC inhibitors in NSCLC.
4.
Because the earliest PKC inhibitors do not exhibit an isozyme-specific inhibitory profile, it is difficult to apply well-defined pharmacodynamic endpoints to measure their activity in patients. For instance, the activity of UCN-01 was found to be dependent on the phosphorylation status of Rb . Similarly, PKC412 was found to be active in AML cells with a particular mutation. These two observations raise the question of whether patient selection would have improved the outcome of the first phase I studies. Perhaps, if patients had been appropriately selected, a different trial design with a focus on pharmacokinetic/ pharmacodynamic (PK/PD)assessment would have more appropriately estimated the activity of these PKC inhibitors. Instead, the original development had to rely on establishing the MTD dose level prior to moving into phase II development. In fact, this alternative approach was subsequently pursued for UCN-01, but by that time the interest level for this molecule had dropped and was superseded by other more attractive compounds in cancer therapy .
5.
Furthermore, the relevance of PKC expression and its isoenzymes or their effect on downstream proteins has not been studied sufficiently in human tumor tissue samples. In comparison to the EGF and VEGF pathway, little is known about the PKC expression and its activation pathways in humans. This lack of comprehensive assessment of PKC and its activation pathways in human lung cancer tissue may have contributed to the failure of specific PKC inhibitors in the clinical investigation, such as aprinocarsen. Assuming that PKC-a expression was correlated with clinical outcome as cell line studies suggested ,inhibition of PKC-a expression with aprinocarsen should have resulted in clinical benefit. This assumption was not confirmed in larger phase III studies Whether this was a result of insufficiently blocking PKC-a levels during administration of aprinocarsen (i.e., an unfavorable PK/PD relationship), or whether the expression of PKC-a was only relevant to the tumor growth within a small patient population enrolled on the larger phase III studies (i.e., leading to the underestimation of the required study sample size), cannot be determined today. But, these experiences underscore the need for designing clinical studies with PKC inhibitors differently than in the past, including the use of PK/PD modeling in early studies. They also suggest that integrating strategies to identify patients who may benefit from PKC inhibitor treatment will be valuable tools to determine the activity of PKC inhibitors in NSCLC patients.
6.
Some of these lessons have been applied to the development of the PKC-b inhibitor, enzastaurin. Enzastaurin was originally developed as an antiangiogenic agent, based on implication of PKC-b in angiogenesis and its preclinical activity . One of the striking differences of enzastaurin compared to the other PKC inhibitors investigated clinically is its favorable toxicity/tolerability profile. In the first study in cancer patients, no clinically relevant grade 3/4 toxicities were observed . Also, the subsequent safety review of about 130 patients enrolled in the early phase clinical trials indicated few grade 3/4 drug-related toxicities (2/134, or 2%). This favorable tolerability profile has resulted in a more attractive development path for enzastaurin compared to the more toxic nonspe- cific PKC inhibitors. However, the lack of not having established an MTD has been challenged by many oncologists and casts some doubt as to whether the actual antitumor dose has been or can be achieved Therefore, it was critical for the enzastaurin program to prove that its targeted exposure levels of 1400 nM was associated with significant inhibition of PKC phosphorylation. The favorable tolerability/toxicity profile and the evidence of a PK/PD relationship in patients has allowed the enzastaurin development to proceed in a different fashion than the previous PKC inhibitors.
7.
While the PK/PD relationship has been generally addressed for enzastaurin, the greatest challenge for the clinical development of enzastaurin remains in identifying the patient population likely to benefit from this treatment. This will require the discovery and validation of predictive biomarkers, which for most biologic agents have been unpredictable and elusive. The process of biomarker discovery and validation in treatment of metastatic NSCLC continues to be hindered by the inaccessibility of tumor tissue for analysis in the majority of the patients. Optimizing the success of molecular targeted therapies in NSCLC will require a concerted effort to overcome inherent hazards and reluctance associated with performing biopsies of lung cancer or metastatic lesions. Alternatively, one should consider the development of high sensitivity assays to detect tumor-related biomarkers in the circulating bloodstream, such as circulation tumor cell fragments or whole cells. Although predictive markers of response to enzastaurin have not yet been determined, mechanisms of anticancer activity have been determined in preclinical studies. Enzastaurin treatment in vitro suppresses the phosphorylation of GSK-3bSer9 , ribosomal protein S6S240/244 , and AKTThr308 , and may thus directly inhibit cancer cell growth. In in vivo studies, enzastaurin treatment suppresses GSK-3b phosphorylation in both tumor tissue and in PBMCs, suggesting that GSK-3b phosphorylation may serve as a reliable pharma- codynamic marker for enzastaurin activity. Whether or not the presence or degree of GSK-3b or AKT phosphorylation prior to enzastaurin might predict response to treatment has not been reported, and will be explored in upcoming clinical studies.
8.
In summary, PKC inhibitors have not yet established themselves as a new anticancer drug treatment. The success of PKC inhibitor therapy for cancer will depend on demonstrating inhibition of specific PKC targets, discovering the critical biologic profile in tumors required for its anticancer activity, and creating tests to predict which patients would benefit from treatment. The first step towards this goal has been the evaluation of potent isozyme-specific PKC inhibi- tors. Future studies will need to incorporate tumor biopsies, blood, and/or surrogate tissues to evaluate potential predictive markers, such as GSK-3b AKT, ribosomal protein S6, and IL-8. PKC inhibitors will require much broader clinical and scientific investigations before they can be optimally utilized, but they offer the possibility of multi-valent anticancer effects, including induction of apoptosis, cell cycle inhibition, and interruption of angiogenesis, and have already demon- strated promising clinical efficacy.

PKC抑制剂为肿瘤领域研究热点，该文段作者阐述了PKC抑制剂在肿瘤领域尤其是NSCLC治疗中的研究进展，文中提供了目前为止全世界该类药物最新的临床研究成果。
现征集优秀战友进行翻译校正，加分从优！视数量和质量酌情1-5分加分，可分段认领，请认领者于24小时内完成。