讨论肺腺癌相关靶点，对应药物及新药临床进展(新增PF-299804））

瓶子 发表于 2011-6-13 11:29

                               
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1：特/易耐药后仅有7.4%的人群对BIBW有反应

这是不是说特，易耐药，也不用考虑用bibw2992了？不是针对 ...

Unfortunately, this trial failed to show a survival benefit from afatinib over placebo as a single agent.  There were also only 7.4% of TKI-resistant patients who responded to afatinib.

是这么说的 ，相比于安慰剂并没有明显优势。 只有7.4%的TKI耐药人群对阿法替尼有反应

哪里有得卖？

Exelixis, Inc. reported expanded Phase 2 study data with respect to cabozantinib (XL184) use in advanced ovarian cancer patients at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting . The overall solid tumor Phase 2 safety and tolerability data refers to six deaths, including two ovarian cancer patients.

On May 19, 2011, we reported promising cabozantinib phase 2 solid tumor (including ovarian) data, which was presented at an ASCO press briefing held in advance of the 2011 ASCO Annual Meeting. As noted in our May 19 article, cabozantinib demonstrated excellent activity against several solid tumors, including ovarian cancer. In addition, we reported that cabozantinib showed promising activity in ovarian cancer patients independent of prior response to platinum drug-based therapies.

Ronald J. Buckanovich, M.D., Ph.D., Assistant Professor, Departments of Internal Medicine & Obstetrics and Gynecology, University of Michigan, presented the expanded cabozantinib Phase 2 data relating to use of the drug in advanced ovarian cancer patients, on June 4 at the 2011 ASCO Annual Meeting.

Ovarian Cancer Patient Population & Overall Response Rate


(Image Source: Exelixis, Inc.)
The cabozantinib trial is an ongoing phase 2 adaptive randomized discontinuation trial. As of the February 11, 2011 cut-off date, accrual in the cabozantinib study cohort was complete at 70 patients.

The 70 patients enrolled in the ovarian cancer cohort received oral cabozantinib (100 mg) daily over a 12 week “Lead-in Stage.” These patients had a minimum follow-up of at least 12 weeks and were thus evaluable for safety and the primary efficacy endpoint of response per RECIST (Response Evaluation Criteria in Solid Tumors).

Patient tumor response was assessed every 6 weeks. Receipt of cabozantinib treatment beyond the 12 week open label Lead-in Stage was based upon patient response: (1) patients with a partial response (PR) or complete response (CR) continued taking cabozantinib, (2) patients with stable disease (SD) were randomized to the cabozantinib treatment arm or the placebo treatment arm (collectively referred to as the “Blinded Randomized Stage”), and (iii) patients with progressive disease (PD) discontinued study treatment. The study primary endpoint was overall response rate (ORR) per RECIST in the Lead-in Stage, and progression free survival (PFS) in the Blinded Randomized Stage. Accrual in any cohort could be halted for high ORR or PD.

Approximately half of the 70 patients enrolled in the cohort were considered platinum drug-refractory/-resistant (49%), defined as a platinum drug-free interval of 6 months or less, and the remainder of patients (51%) had platinum-sensitive disease based on a platinum-free interval greater than 6 months.

The baseline patient tumor histologic characteristics are as follows: serous ovarian cancer (79%), clear cell ovarian cancer (4%), endometrioid ovarian cancer (6%), and other forms of ovarian cancer (11%)

More than half the patients (57%) received 2 or more prior lines of platinum therapy prior to trial enrollment. Some patients also had additional prior lines of therapy with agents such as pegylated liposomal doxorubicin (brand name: Doxil®) or topotecan (brand name: Hycamtin®) (32%), gemcitabine (brand name: Gemzar®) (29%), and VEGF (vascular endothelial growth factor) pathway inhibitors (10%).

Evidence of objective tumor regression was observed in 73% of patients with at least 1 post-baseline medical imaging scan. The best overall response rate per RECIST criteria was 24% (16 PRs and 1 CR). The overall Week-12 disease control rate (DRC = CR + PR + SD) was 53%. The Week-12 DCRs in the platinum drug-refractory, -resistant, and -sensitive groups were 36%, 39%, and 67%, respectively.

Based on an observed high rate of clinical activity, randomization was halted, and randomized patients were unblinded.  At this point, the unblinded randomized patients that were treated with placebo were allowed to “cross-over” to treatment with cabozantinib. Disease stabilization was experienced by some ovarian cancer patients who had progressive disease prior to treatment cross-over.

“These latest results in metastatic ovarian cancer demonstrate the potential broad utility of cabozantinib beyond bone-predominant types of cancers such as castration-resistant prostate cancer. The high rates of durable response with our dual inhibitor of MET and VEGFR2 compare favorably to those of other single-agent targeted therapies and cytotoxic agents in development,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “These results underscore the potential of cabozantinib in metastatic ovarian cancer, and we are in discussions with leading cooperative groups to plan further evaluation of cabozantinib in randomized trials for this indication.”

Activity in Platinum Drug-Sensitive, -Refractory, and -Resistant Disease


Ignace Vergote, M.D., Ph.D., senior author of the cabozantinib (XL184) ASCO presentation & Chairman, Leuven Cancer Institute, University of Leuven, European Union

(Image Source: Exelixis, Inc.)
Two of 11 patients (18%) with platinum refractory disease, defined as a platinum-free interval of <1 month, achieved a confirmed response (1 CR and 1 PR).

In the subset of patients with platinum-resistant disease, defined as a platinum-free interval of 1-6 months, 5 of 23 (22%) achieved a PR.

Ten of 36 patients (28%) with platinum sensitive disease achieved a PR.

A total of 37 patients experienced reductions in the ovarian cancer tumor marker CA-125 (cancer antigen-125), including 8 with decreases greater than 50%. There is no consistent concordance between CA-125 changes and tumor regression. The median duration of response has not yet been reached with 36 weeks of median follow-up.

“The continued activity of cabozantinib in a larger population of ovarian cancer patients is very encouraging, especially with respect to the clinical benefit observed in both platinum-sensitive and platinum-resistant/refractory disease. This activity profile has not been observed with other single-agent TKIs [tyrosine kinase inhibitors], and cabozantinib has the potential to be an important new treatment for ovarian cancer,” said Ignace Vergote, M.D., Ph.D., senior author of the presentation and Chairman of the Leuven Cancer Institute at the University of Leuven, European Union. “The high rate of disease control in platinum-resistant and platinum-refractory disease suggests that cabozantinib may help to address the substantial unmet medical need faced by patients who have sub-optimal responses to platinum-based therapies. I believe that further evaluation will help to define the potential role of cabozantinib in the treatment of ovarian cancer.”

General Safety & Tolerability Data

Safety data are available for the 70 patients in the Lead-In phase of the cabozantinib study. The most common CTCAE (Common Terminology Criteria for Adverse Events) grade 3 or 4 adverse events (AEs), regardless of causality, were diarrhea (10%), fatigue (9%), palmar-plantar erythrodysesthesia  syndrome (also referred as “hand-foot syndrome”)(7%), vomiting (4%), abdominal pain (3%), hypomagnesemia (3%), and nausea, constipation, rash, increased transaminase, and hypertension (each 1%). At least one dose reduction was reported in 37% of patients. Less frequent important medical events, regardless of causality, were hemorrhage (11% all CTCAE grades, 0% CTCAE grade 3 or 4), venous thrombosis (6% all CTCAE grades, 4% CTCAE grade 3 or 4), and gastrointestinal perforation (6% all CTCAE grades, 0% CTCAE grade 3 or 4).

To access the cabozantinib clinical study data information, please visit www.exelixis.com/sites/default/f ... 1-XL184-Ovarian.pdf

Six Deaths Reported (Including Two Ovarian Cancer Patients)

If you examine the Exelixis press release dated June 4 (entitled, Exelixis’ Cabozantinib Demonstrates Encouraging Clinical Activity in Patients with Metastatic Ovarian Cancer – Disease control rate of 53% at week 12, response rate of 24%), which addresses data for cabozantinib use in advanced ovarian cancer patients, pay particular attention to the wording under the heading entitled, “Safety and Tolerability.”  Within the wording set forth under that heading, you will find the following statement: “Two cabozantinib-related grade 5 AEs [adverse events], one enterocutaneous fistula and one intestinal perforation, were reported after the Lead-In phase.” Pursuant to the CTCAE guidelines, a “grade 5 adverse event” is defined as “death related to AE [adverse event].”

We should also note that the two ovarian cancer deaths were summarized briefly in the ASCO presentation regarding cabozantinib use in advanced ovarian cancer.

The reporting of all six deaths is set forth in the Exelixis press release, dated June 5, 2011 (entitled, Exelixis’ Cabozantinib Demonstrates Broad Clinical Activity in Multiple Tumor Types), in similar fashion. Within this release, the sentence provided under the heading “Safety and Tolerability” states: “There were 6 (1%) cabozantinib-related grade 5 [adverse] events, all of which were reported after the Lead-In phase of the trial: respiratory compromise (breast cancer), hemorrhage (NSCLC [non-small cell lung cancer]), enterocutaneous perforation (ovarian cancer), intestinal perforation (ovarian cancer), gastrointestinal hemorrhage (pancreatic cancer), and death (CRPC [castrate resistant prostate cancer]).”

Exelixis Chief Executive Michael Morrissey said the safety statistics are consistent with targeted cancer therapies like cabozantinib that block a pathway used by tumor cells to secure blood vessels.

Cowen & Co analyst Eric Schmidt said the rate of cabozantinib treatment-related deaths — 1 percent — was “no different from what we have seen for every other Phase 1 and 2 trials here at ASCO.”

“While drug safety is of less concern in cancer indications than in others, the apparent morbidities associated with cabo[zantinib] use will confound interpretation of clinical benefit in a trial designed to show anything less than overall survival,” Canaccord analyst George Farmer said in a research note.

In a note to investors, Piper Jaffray analyst Edward Tenthoff said: ”The company is exploring lower doses, but the concern is that cabo[zantinib] will not retain the impressive efficacy seen to date.”

Mr. Morrissey said Exelixis plans to move forward with the current daily 100 mg dose of the drug.

Dr. Nicholas J. Vogelzang (Director, Comprehensive Cancer Centers of Nevada) Discusses Mortalities in the Cabozantinib (XL184) Trial



XL184起始服用剂量：100mg

Molecular Profiling Defines New Potential Targets for Lung Cancer Treatment
Appropriate patient selection might influence cost of care, further study needed

The collaborative efforts of members of the Lung Cancer Mutation Consortium (LCMC) demonstrate that although lung cancer may be a disease with one name, genetically it is very heterogeneous. Preliminary results of a study conducted by the LCMC (Abstract CRA7506) are the initial reports of the occurrance of 10 driver mutations for lung adenocarcinoma in 1,000 patients.

Mark G. Kris, MD, of Memorial Sloan-Kettering Cancer Center, presented findings at yesterday’s Oral Abstract Session: Lung Cancer — Metastatic/Non-small Cell. In addition to quantifying the presence or absence of driver mutations, the information was used in real time either to select erlotinib for patients with EGFR mutations or to recommend an appropriate clinical trial of an agent targeting the specific mutation identified. "Understanding the biology of the tumor can lead to better, more effective treatment for the patient," Dr. Kris said.

Investigators tested tumors from patients with lung adenocarcinoma in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS mutations using standard multiplexed assays and FISH for EML4-ALK rearrangements and MET amplifications. All patients had stage IIIB/IV lung cancer and a performance status of 0 to 2.

"Understanding the biology of the tumor can lead to better, more effective treatment for the patient."  
— Mark G. Kris, MD


In this group of 516, a single driver mutation was detected in 54% (280) of tumors. The most common mutations found were KRAS (114, 22%), EGFR (89, 17%), and EML4-ALK rearrangements (38, 7%). Other mutations found included BRAF (9), PIK3CA (6), MET amplifications (3), HER2 (3), MEK1 (2), NRAS (2); no AKT1 mutations were found. Ninety-seven percent of mutations were mutually exclusive.

The network of 14 participating institutions was established quickly, and the ability to test for these mutations consistently around the United States is a benefit that will outlive the grant.

"Our goal was to develop testing capability at every site," Dr. Kris said. He noted that seven of the 14 sites developed this capability specifically for the trial, and that this testing will continue. "This is the only time that every test for every mutation on every sample was done.”

In his discussion, Ramaswamy Govindan, MD, of the Alvin J. Siteman Cancer Center and Washington University School of Medicine, noted that knowledge in the area of cancer genetics is growing rapidly, as is the number of targeted therapies. An appropriate match between the two is critical, and the work of the LCMC is an important step.

"If you give targeted drugs to targeted patients, they do quite well," he said.

The link between patients with mutations and appropriate trials is an important component, as is the development of trials testing targeted agents. Only 8% of non-small cell lung cancer studies are currently biomarker driven.

The cost of cancer care might be contained if targeted agents are used only for patients who are appropriate candidates. A French study of EGFR testing for patients prior to treatment with gefitinib showed a cost savings, even with the cost of testing factored in. More studies of new potential targets and personalized adjuvant therapy also are needed, Dr. Govindan concluded.


肺癌中可探查到的基因突变（54%）：


KRAS (114, 22%)
EGFR (89, 17%)
EML4-ALK rearrangements (38, 7%).
BRAF (9), PIK3CA (6), MET amplifications (3), HER2 (3), MEK1 (2), NRAS (2);

也就是说还有46%肺癌患者是检测不到明确基因突变的。。

　在2011年美国临床肿瘤学会（ASCO）年会上，无论是医学科学还是癌症教育的报告，均贯穿了今年的会议主题——“患者，路径，进展”（Patients, Pathways, Progress）。在包括肺癌在内的各类肿瘤研究领域，基于分子标志物的转化性研究和临床研究均取得了重大进展。表皮生长因子受体（EGFR）基因突变及间变性淋巴瘤激酶（ALK）基因融合变异与相应靶向抑制剂的关系均已得到临床研究的证实，而针对肺癌中MET等分子靶点的治疗研究也取得了初步进展。其他相关分子变异的鉴定和药物研发的速度越来越快，肺癌的临床诊治模式也将发生较快的改变。

　　会上，ASCO主席斯莱奇（Sledge）及美国国立癌症研究所（NCI）主任瓦默斯（Varmus）都指出：“基于遗传变异的肿瘤治疗时代已经到来。” 并且，他们均表示未来要加强分子标志物的研究，加深对肿瘤发生发展分子机制的理解，从而促进肿瘤驱动分子突变（driver mutation）的鉴定及相关药物的研发。Varmus表示，尽管NCI 2011年的预算缩减，但NCI仍然愿意将有限资金用于全基因组测序等研究计划，以便从临床样本中发现新的靶点用于药物临床试验从而寻找可能的治疗策略。下面，本文就2011年ASCO会议上肺癌相关的转化性研究进展作一报道。

　　ALK分子突变型肺癌治疗：疗效显著，仍需进一步探索

　　在今年ASCO年会上，坎布里奇（Cambridge）对肺癌中ALK小分子抑制剂crizotinib的Ⅰ期临床试验（NCT00585195或A808-1001）结果进行了更新。

　　目前该研究入组的非小细胞肺癌（NSCLC）患者例数已达119例，中位无进展生存（PFS）期达到10个月，客观反应率达61%，中位反应时间为48周，而中位生存时间达1年的患者比例为81%。该研究的数据仍在不断更新中。

　　综合去年、前年ASCO年会上的报告不难看出，ALK抑制剂在ALK融合型肺癌中一直保持着良好的疗效。患者耐受性较佳，主要不良反应为视觉障碍等。疾病进展（PD）主要表现为脑转移和肺部靶病灶进展。目前，该领域的相关后续Ⅲ期临床研究（二线、三线、一线）也正在进行中。

　　不过，有关crizotinib的这项研究也同样给我们提示了一些值得关注的问题。首先，已有专家提出，对不同的ALK融合变异体，crizotinib的疗效也可能不同。如果这在未来研究中得到证实的话，那么基于荧光原位杂交（FISH）检测技术的ALK融合检测分析将必须要经过逆转录聚合酶链式反应（RT-PCR）和（或）测序技术分析，以明确变异体的类型，这无疑还须开展进一步研究以确立相关临床检测适用技术。

　　其次，患者接受ALK抑制剂治疗后出现耐药的机制是什么？目前已知的可能机制包括ALK酪氨酸激酶（TKI）区L1196M、C1156Y的二次位点突变及潜在的F1174L突变，而其他的耐药机制类型仍需进一步展开鉴定和研究。

　　此外，耐药后的处理对策又将如何？目前已知热休克蛋白（HSP）90是ALK等多种激酶受体或胞内激酶蛋白的辅助分子，HSP90抑制剂（IPI-504）已初步显示出对ALK抑制剂耐药的肺癌患者具有一定的疗效。

　　目前，其他较crizotinib具更强结合力的ALK抑制剂也正在研发过程中，有望为将来肺癌的治疗提供更多的选择。而在各国学者的努力下，围绕ALK融合型肺癌亚型的鉴定，靶向患者检测技术的建立，ALK抑制剂的研发、相关耐药机制和耐药后治疗策略等一系列科学问题正得到快速的确立、发现和研究。可见，有关ALK的一系列科学进展速度之快令人称赞，这些探索都将为最终真正根治这种分子亚型的肿瘤提供各种条件。

美国学者斯皮格尔（Spigel）报告，一项针对肺癌MET分子靶点的Ⅱ期临床研究比较了MET单抗（OAM4558g）联合厄洛替尼与安慰剂二/三线治疗ⅢB/Ⅳ期NSCLC的疗效。

　　该抗体主要是通过封闭肿瘤细胞表面MET受体与其配体HGF的结合而抑制细胞生长。在该研究中，MET受体的阳性表达被定义为50%以上肿瘤细胞中免疫组化（IHC）染色强度为中度至强染色。

　　结果发现，在意向治疗（ITT）人群中的MET受体阳性亚组，OAM4558g+厄洛替尼组患者的PFS期（2.9个月对1.5个月，P=0.04）和总生存（OS）期（12.6个月对3.8个月，P=0.002）都显著优于安慰剂+厄洛替尼组。

　　而在MET受体阴性亚组中，OAM4558g联合厄洛替尼则似乎对患者有害，OAM4558g+厄洛替尼组与安慰剂+厄洛替尼组的PFS期分别为1.4个月和2.7个月（P=0.05），OS期分别为8.1个月和15.3个月（P=0.16）。OAM4558g的主要不良反应包括外周水肿等。

　　该研究提示，MET单抗能够在肺癌患者体内有效抑制MET信号传导通路，患者耐受性佳。本研究的成功之处在于预设的MET受体表达水平检测阳性患者能够显著获益，提示MET蛋白表达亚群是该抗体的靶向人群，再次印证了在非选择人群中，具有明确靶点药物的有效作用往往可能被稀释而得不到阳性结果。而该研究采用IHC检测MET表达的检测技术和评价方法均适合进一步开展相关临床研究。该研究的作者表示，2011年，他们将在MET阳性患者群体中进一步开展相关Ⅲ期临床试验。那么，就让我们期待着该试验的结果吧！

　　基于分子靶点的肺癌分子分型：快速深化，由单基因检测向多基因或全基因组分析转变

　　多分子变异分析的探索

　　本届大会的一个重要特点就是基于分子标志物的研究明显增多，而且这些标志物往往就是可以干预肿瘤生长的分子靶点。肿瘤学家对肿瘤的理解已经进入分子水平，临床诊治实践也已走入分子时代。这次大会比较突出的分子研究涵盖了黑色素瘤、肺癌等恶性肿瘤，但是针对非选择患者的靶向药物临床试验却基本都得到阴性结果。在目前所有肺癌临床研究中，使用分子标志物筛选患者的试验仅占8%左右。

　　在本届ASCO年会特别安排的“个体化治疗：药物选择的系统生物学方法”专场上，美国学者卡利法诺（Califano）指出，通过新的高准确度、高通量的分子变异谱筛选技术可明确特定肿瘤细胞中整合异常信号的生物学调节过程，从而实现个体化治疗。通过基于分子变异谱的反向工程算法可明确肿瘤生长依赖的整合信号通路关键分子，而针对该分子的治疗会成为重要策略之一。Califano等分析发现，多型性胶质母细胞瘤细胞经同时活化C/EBP和STAT3来促进细胞移动、侵袭和转移。也有针对肺癌的研究提示，多个分子变异的信号最终都会整合到PI3K/AKT/mTOR或RAS/MAPK中从而使这两条通路活化。

　　多基因突变同步分析的可行性

　　在针对“肺癌全基因组测序：一名临床医师应该了解的内容”的专题讨论中，有专家指出，除了现有的EGFR、KRAS、ALK等基因突变或融合之外，新一代全基因组测序技术的使用可能使我们发现更多的基因突变，包括单碱基变异、小片段的插入或缺失、倒位及转座等。美国学者马尔迪斯（Mardis）指出，全基因组测序必将成为临床实践的一部分。而且基因组序列信息分析也将有助于制定基于分子分型的肺癌临床标准治疗方案。

　　ASCO于今年首次颁发的“人道主义奖”获得者克里斯（Kris）代表肺癌突变联盟（LCMC）报告了基于全基因组或多重分子分型治疗的研究结果。该研究在近1000例肺腺癌患者中同步分析了10个驱动基因突变状态，并实时基于EGFR或其他分子突变将患者分配至EGFR-TKI（厄洛替尼）或LCMC链接的针对分子变异相应临床试验中行靶向治疗。目前研究针对516例患者样本完成了分子检测，其中280例（54%）检测到单个驱动基因的变异。该研究的主要目的是促进肿瘤分子分型发展，并最终在14家参与中心都建立分子检测平台（已有11家中心获得了检测能力），帮助患者进行分子诊断及筛选合适的治疗手段。该研究表明了临床上进行多个驱动基因突变同步分析的可行性，其临床疗效等结果有待于进一步观察。

　　针对特定靶点的个体化靶向治疗探索

　　另一项基于分子检测的个体化治疗研究也获得了初步但令人瞩目的成果。美国学者钦布里多（Tsimberidou）报告了一项基于多个分子突变检测的Ⅰ期研究结果。1114例患者中有955例可接受分子突变分析，其中852例检测到了分子变异，175例仅有一个分子变异。将该175例患者入组36项临床试验进行匹配的靶向治疗，而另116例未检测到突变者被分配到49项非匹配靶向治疗临床试验。结果显示，匹配治疗组的客观反应率达27%，显著高于非匹配治疗组的5%（P<0.0001），且匹配治疗组的中位生存时间为13.4个月，较非匹配治疗组显著延长（9.0个月，P=0.017）。

　　由于这是在经过了2～3线治疗群体中得到的结果，作者指出，发现分子变异靶点、选择针对该靶点用药的方案明显优于现有的标准治疗方案。从数据看，该研究确实取得了较大突破，基于分子变异检测的个体化靶向治疗可显著提高整体疗效。然而美国弗吉尼亚大学癌症中心弗拉卡索（Fracasso）也点评了其中不足，包括原发与复发病灶中的分子变异不同带来的不确定性，潜在的既往治疗程度会影响分子变异状态分析，未具体分析每种分子变异的疗效，只有一个分子靶点变异的入组标准等，这些都可能使研究结果存在混杂效应或设计上的不足。尽管如此，该研究还是给我们带来很多启发，提示是时候改变传统诊疗模式了，当然这需要肿瘤学家切实思考临床上针对分子靶点制定个体化治疗策略的优越性并加以验证。

多分子变异分析的优点主要体现在以下三方面。

　　1.多基因检测或全基因组序列分析可以发现新的药物治疗靶点。对于那些没有明确有效治疗方案的癌症或经治后无明显对策的肿瘤进行检测，可以发现新的干预靶点进行治疗。例如，对于肉瘤等以前没有理想治疗策略的肿瘤，通过基因组测序技术可以发现其常见PIK3CA突变，PIK3CA抑制剂可能有效。对于肺鳞癌，也有研究结果显示，FGFR、DDR2等受体通路常见变异活化，提示未来肺鳞癌的个体化靶向治疗首先基于这些信号传导通路。另有研究显示尼古丁受体（nAChR）等在吸烟肺癌患者中的作用不仅与吸烟行为有关，而且对持续活化的NR途径进行干预可能对吸烟肺癌患者的治疗具有一定的价值。

　　2.多数经过一线或多线治疗的晚期肿瘤患者，在接受了所有现有临床药物治疗之后，经过分子变异谱分析后仍然能够找到其相应的分子变异靶点，从而找到有效治疗策略。

　　3.多分子变异检测技术的进步快速，其检测成本也将进一步下降，仍在革新发展的技术最终将使得临床上对患者肿瘤组织进行全基因组或少数基因的靶向深度测序成为可能，最终为全面制定以分子分型为基础的个体化治疗策略提供技术支持。

　　虽然预后或疗效预测相关分子标志物或靶点在各类肿瘤中的鉴定和检测技术的建立将是未来的研究重点，但针对肿瘤的高通量分子变异分析也有诸多陷阱，从大量的数据分析中找出真正具有驱动作用的分子靶点具有较大的难度。例如，全基因组关联分析（GWAS）或全基因组测序分析技术并不能完全区分相关基因在肿瘤发生或进展过程中是关键的驱动分子或仅是伴随的变异分子。因而，我们需要对这些基因组变异进行功能解剖分析，可以通过基因表达调控实验技术、协同致死性实验分析、信号通路网络的计算机分析等技术进一步明确这些分子是否是真正参与癌症发生、发展的驱动分子，从而确定其作为治疗靶点的价值，并进行临床试验分析。所有关于协同致死实验的技术平台、生物信息分析技术均需要同步建立起来，方能有效鉴别真正驱动特定肿瘤的变异靶点，而针对该肿瘤弱点的治疗方能奏效。

　　其他肺癌转化性研究进展：肿瘤干细胞……

　　在本届ASCO年会上，多位学者均提及了癌症干细胞（CSC）的相关理论或实验研究，提出CSC如何在肿瘤演进或耐药过程中发挥作用及如何寻找杀灭CSC的靶向药物等均是肺癌等实体瘤研究的重要方向。

　　上皮间质转化（EMT）是参与胚胎发育的生物学过程，在肿瘤对化疗或酪氨酸激酶抑制剂靶向治疗产生耐药的过程中，EMT也有重要作用。EMT与肿瘤细胞去分化而获得干细胞样特征可能相关，而与肿瘤细胞侵袭、转移等生物学过程密切相关。因而，针对EMT的分子机制研究及在不同药物作用下的EMT变化检测均有助于理解肿瘤的发生机制并寻找新的治疗对策。

　　会上，2009年诺贝尔生理学或医学奖得主布莱克本（Blackburn）和米勒（Miller）分别介绍了肿瘤细胞端粒及断裂酶抑制剂在基础、临床研究中的探索现状。目前端粒酶除了与肿瘤细胞端粒长度的维持有关外，还可能通过Wnt等信号通路参与肿瘤的其他信号传导途径。充分研究肿瘤细胞中端粒酶参与的信号途径和作用机制，有助于进一步研究端粒干预治疗策略，而对端粒酶信号途径的深入探讨则是指导临床试验取得成功的关键。

　　ASCO重视基础及转化性研究：著名学者获颁“肿瘤学科学奖”

　　为了表明对肿瘤基础研究的重视，ASCO自2005年开始设立“肿瘤学科学奖（Science of Oncology Award）”，今年该奖被授予了著名的罗伯特·温伯格（Robert Weinberg）教授。

　　来自美国麻省理工大学白头研究所的Weinberg对肿瘤研究作出了杰出贡献。自1980年发现了首个人癌基因Ras后，1986年他又率领其团队分离鉴定了首个人抑癌基因（视网膜母细胞瘤基因）。这些发现阐述了癌细胞生长依赖的分子遗传学基础，为癌症病因提供了崭新理解方式，并为后来临床治疗和药物研发提供了革命性启示。Weinberg已成为当今肿瘤遗传病因的权威人士，他与哈纳汉（Hanahan）合著的综述文章《癌症的功能特征》（Hallmarks of Cancer）及其更新版已成为全世界肿瘤研究者的必读文章，并持续影响着当今肿瘤相关基础和药物研究。

　　在今年ASCO年会上，Weinberg围绕肿瘤转移相关的EMT过程、肿瘤干细胞及潜在的治疗对策进行了精彩演讲。他发现，肿瘤细胞在转移、侵袭的过程中往往伴有明显的EMT分子特征，Vimentin、Snail等间质成分标志物的表达又与肿瘤干细胞标志物CD44的出现具有一定相关性，提示肿瘤干细胞与EMT表型细胞有一定的相似性。他的研究组通过通量筛选已发现了可有效杀伤肿瘤干细胞的药物，目前尚处在研究中。我们对此拭目以待，期望出现理想的结果。(广东省肺癌研究所 广东省人民医院 广东省医学科学院 张绪超 吴一龙 发自美国芝加哥)

　ASCO 2011报道：Riely等的一项研究报告表明，在先前接受过治疗的转移性非小细胞肺癌（NSCLC）患者中，IPI-504联合多西他赛有临床治疗活性，且患者对治疗耐受性良好。

　　IPI-504是17-丙烯氨基-17-去甲氧基格尔德霉素（17-AAG）的一种水溶性类似物，是一种静脉给药的热休克蛋白90（Hsp90）抑制剂，可抑制多种癌基因蛋白突变或扩增。在鼠类异种移植肿瘤模型中，IPI-504联合紫杉烷类被证明活性增强。

　　该研究是一项Ⅰb期扩展试验，旨在评价IPI-504联合多西他赛在NSCLC伴Karnofsky体能状态（PS）≥70患者中的应用。患者被病理学检查确认为转移性NSCLC，所有患者先前接受了1～2种化疗方案治疗，但先前未接受多西他赛治疗。患者接受每3周1次多西他赛75 mg/m2静脉输注和每周1次IPI-504 300 mg/m2静脉输注治疗。所有患者接受了安全性、药动学和肿瘤缓解评估[实体瘤疗效评价标准（RECIST）]。研究需要对归档组织样本进行KRAS基因分型。

　　结果显示，23例入组该研究的患者接受了平均4个周期（范围：1～13个周期）的治疗。中位年龄为61岁，13例（57%）为女性，18例（78%）为当前或之前吸烟者，中位烟草暴露为30 包-年。大部分不良事件为1或2级，最常见的治疗相关不良事件为疲劳（总体为57%，4%≥3级）、腹泻（35%，9%）、恶心（30%，13%）、呕吐（30%，13%）、中性粒细胞减少症（30%，30%）和贫血（26%，4%）。联用IPI-504改变了多西他赛药动学。23例患者中的6例（26%）部分反应（PR）。总人群和接受探索性分析的亚组功效分析如下（表）。