恶性黑色素瘤治疗(基因突变靶向治疗)

Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

Keith T. Flaherty, M.D., Igor Puzanov, M.D., Kevin B. Kim, M.D., Antoni Ribas, M.D., Grant A. McArthur, M.B., B.S., Ph.D., Jeffrey A.

Sos man, M.D., Peter J. O'Dw yer, M.D., Richard J. Lee, M.D., Ph.D., Joseph F. Grippo, Ph.D., Keith Nolop, M.D., and Paul B. Chapman,

M.D.

BACKGROUND

The identification of somatic mutations in the gene encoding the serine–threonine protein kinase B-RAF (BRAF)

in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease.

Metastatic melanoma is an aggressive disease for which there are few effective therapies. The two therapies

approved by the Food and Drug Administration, high-dose interleukin-2 and dacarbazine, are each associated

with response rates of only 10 to 20% and a small percentage of complete responses; neither is thought to

improve overall survival.1,2 In randomized trials, the median survival among patients treated with dacarbazine

was less than 8 months.3,4

A search for mutations in a component of the mitogen-activated protein (MAP) kinase pathway in a large panel of

common cancers revealed that 40 to 60% of melanomas, and 7 to 8% of all cancers, carry an activating mutation in the gene encoding the serine–threonine protein kinase B-RAF (BRAF). 5-15 Ninety percent of reported BRAF mutations result in a substitution of glutamic acid for valine at amino acid 600 (the V600E mutation). This BRAF mutation constitutively activates BRAF and downstream signal transduction in the MAP kinase pathway. BRAF mutations are also found in 40 to 70% of papillary or anaplastic thyroid cancers6-8,16-18 and in a small percentage of several other types of tumor.

PLX4032 (Plexxikon; RG7204, Roche Pharmaceuticals) is a potent inhibitor of BRAF with the V600E mutation.

Preclinical studies showed that PLX4032 and its analogue PLX4720 inhibit the kinase activity of BRAF with the V600E mutation at low nanomolar concentrations, abrogate signaling through the MAP kinase pathway, and

block proliferation of cells carrying BRAF with the V600E mutation in vitro at high nanomolar concentrations.17,18 Orally administered PLX4720 inhibits the growth — and, at higher doses, induces the regression — of human melanoma tumors transplanted into immunocompromised mice. None of these effects are observed in normal tissues or in tumor cells that lack a BRAF mutation.

We conducted a trial of the use of PLX4032 in patients with metastatic cancer. The primary goals were to define the safety and pharmacokinetic characteristics of treatment with continuous, twice-daily administration of

PLX4032, to determine the maximum dose that could be administered until adverse effects prevented further

dose increases (i.e., the recommended phase 2 dose), and to determine the objective response rate, the duration of response, and the rate of progression among patients who had melanoma tumors with the V600E BRAF

mutation and who were given the recommended phase 2 dose of PLX4032.

METHODS

Study Design

The study was sponsored by Plexxikon and Roche Pharmaceuticals, which provided the study drug. The study was designed by two academic authors and one industry author. All authors made the decision to submit the

manuscript for publication. All authors analyzed the data, prepared the manuscript, and vouch for the completeness and accuracy of the data and analyses. The study was conducted in accordance with the protocol.

Dose-Escalation Phase

PLX4032 was initially in a crystalline formulation. In the dose-escalation phase of the study, which involved several consecutively enrolled groups of three to six patients, the first group received 200 mg of PLX4032 by mouth daily; subsequent groups received the drug at higher doses, according to a dose-escalation scheme. This formulation was found to have poor bioavailability (see the Results section), and enrollment for the

dose-escalation phase was halted while the drug was reformulated as a highly bioavailable microprecipitated bulk powder, initially as a 40-mg capsule and subsequently as 80-mg and 120-mg capsules, as well as 240-mg tablets. Enrollment was resumed, with newly enrolled patients receiving the microprecipitated-bulk-powder formulation at a dose of 160 mg (two 80-mg capsules) twice daily, with subsequent escalation.

Patients received continuous therapy with PLX4032 unless unacceptable side effects or disease progression occurred. Doses were not escalated unless the patients receiving the highest current dose had been observed for at least 4 weeks and dose-limiting side effects had been reported in fewer than a third. Dose escalation in a given patient was permitted if the safety and adverse-effect profile had been established for the next highest dose. The recommended phase 2 dose was defined as the highest dose at which no more than one of six patients had dose-limiting side effects.

Extension Phase

Once the recommended phase 2 dose had been identified, an extension cohort was treated at this dose. In this cohort, all patients had melanoma and a prospectively identified V600E BRAF mutation. The primary objective in the extension cohort was to determine the response rate. Secondary objectives were to define the toxicity and pharmacokinetics of PLX4032 more precisely and to obtain data on pharmacodynamic effects.

Patients

Eligibility criteria included the provision of written informed consent, an age of 18 years or older, solid tumors confirmed histologically that were refractory to standard therapy or for which standard or curative therapy did not exist, Eastern Cooperative Oncology Group performance status score of 0 (able to be fully active and carry out all predisease activities without restriction) or 1 (unable to perform physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, such as light housework or office work),19 life expectancy of 3 months or longer, absence of known progressing or unstable brain metastases, and adequate hematologic, hepatic, and renal function.

The dose-escalation phase of the trial was open to patients with any type of tumor, although patients who had melanomas with the V600E mutation in BRAF were overrepresented because of the selective activity of PLX4032 against such tumors in preclinical testing. For the extension cohort, eligibility was restricted to patients with melanomas harboring a V600E BRAF mutation, as ascertained by means of a polymerase-chain-reaction assay (TaqMan, Applied Biosystems). This assay involves hybridizing a probe specific to the 1799T→A substitution that results in the V600E BRAF mutation with DNA isolated from formalin-fixed, paraffin-embedded tumor tissue and determining the presence or absence of amplification after repeated chain-reaction cycles.20

Study Assessments

Safety evaluations were conducted at baseline, day 8, day 15, day 29, and every 4 weeks thereafter. These evaluations included a physical examination, electrocardiography, laboratory studies that included a complete blood count, clinical chemical testing, and urinalysis. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (version 3.0)

(https://www.sodocs.net/doc/3913843804.html,/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). During the trial, squamous-cell carcinoma, keratoacanthoma type, was observed in several patients (see the Results section). As a result, the protocol was amended to ensure that patients underwent dermatologic evaluations at baseline and every 2 months during the study; computed tomographic (CT) scans of the chest were analyzed for the appearance of new lesions suggestive of a primary cancer.

CT studies were performed at 8-week intervals during therapy in all patients and at the end of the first 4 weeks of therapy in some patients. The findings were judged according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. A complete response was defined as the disappearance of all target lesions, and a partial response as a decrease by at least 30% in the sum of the largest diameter of each target lesion, relative to the corresponding sum at baseline. Progressive disease was defined as an increase by at least 20% in the sum of the largest diameter of each target lesion, relative to the smallest corresponding diameter recorded since the start of treatment, or the appearance of one or more new lesions. Stable disease was defined as the absence of shrinkage sufficient for a partial response and the absence of enlargement sufficient for progressive disease, relative to the corresponding sum at baseline. Progression-free survival was defined as the time from the first day of treatment to the first documentation of disease progression or death, whichever occurred first.

Pharmacokinetic assessments were made on day 1 and day 15 of the first 4 weeks of therapy, and single plasma samples were obtained every 4 weeks during the study. Plasma samples were analyzed by means of

high-performance liquid chromatography, with detection by means of mass spectroscopy.

Patients in the dose-escalation phase who were receiving a dose greater than 160 mg twice daily and patients in the extension cohort underwent 18F-fluorodeoxyglucose–positron-emission tomography (FDG-PET) at baseline and on day 15 of the first 4 weeks of therapy. Selected patients underwent tumor biopsy before the start of therapy as well as on day 15. Biopsy specimens were immediately fixed in formalin for analysis of phosphorylated extracellular signal-regulated kinase (ERK), the protein cyclin D1, and the monoclonal antibody Ki-67 by means of immunohistochemistry. The sampled tumors were cutaneous or superficial lymph-node lesions; except in the case of one patient, sequential biopsy specimens were not taken from the same lesion.

Statistical Analysis

For the primary end point of a partial or complete response in the extension cohort, we calculated that a sample of 32 patients would provide 95% confidence (α=0.05), with 80% power (β=0.20), that an observed response rate of 40% would be consistent with a true response rate of more than 10%, which was considered justification for further study. For this report, January 31, 2010, was the cutoff date for the safety and efficacy follow-up.

RESULTS

Patients

Fifty-five patients were enrolled in the dose-escalation phase of the study (see Fig. 2 in the Supplementary Appendix, available with the full text of this article at https://www.sodocs.net/doc/3913843804.html,); 32 additional patients with metastatic melanoma that carried the V600E BRAF mutation were treated at the recommended phase 2 dose in the extension phase

(Table 1TABLE 1Baseline Characteristics of the Patients, According to Study Cohort.). The majority of patients (49 of 55 [89%]) in the dose-escalation cohort had metastatic melanoma; 3 of the remaining 6 patients had papillary thyroid cancer that carried the V600E BRAF mutation. Screening for the V600E BRAF mutations was not a requirement for study entry during the dose-escalation phase, but throughout the trial, an increasing number of patients were prospectively identified as having the mutation (for a total of 16 of the 21 patients with melanoma who were enrolled in the groups receiving 240 mg twice daily to 1120 mg twice daily).

The initial crystalline formulation of PLX4032 was found to have no dose-limiting side effects or antitumor activity at doses of 200 mg daily to 1600 mg twice daily in consecutively enrolled groups of patients. Since the serum levels detected were lower than the levels predicted in preclinical models to be effective, a

microprecipitated-bulk-powder formulation with substantially higher bioavailability was developed and used for the remainder of the study; the lowest dose was 160 mg twice daily, and escalated doses were 240, 320 or 360, 720, and 1120 mg twice daily (Fig. 2 in the Supplementary Appendix). Patients who had been receiving the crystalline formulation were switched to the microprecipitated-bulk-powder formulation. The protocol allowed the dose to be reduced if side effects developed.

Once the recommended phase 2 dose was established for the microprecipitated-bulk-powder formulation in the dose-escalation cohort, the extension cohort was enrolled. All patients in the extension cohort had melanoma carrying the V600E BRAF mutation (Table 1).

Adverse Events

During the latter part of the dose-escalation phase of the trial, when the microprecipitated-bulk-powder formulation of PLX4032 was used, dose-limiting toxic effects were not observed until a dose of 720 mg twice daily was given. At the next-highest dose given to one group of patients, 1120 mg twice daily, four of the six patients had dose-limiting side effects: three patients with grade 3 rash (two of whom also had grade 3 fatigue) and one

patient with grade 3 arthralgia (Table 2TABLE 2Drug-Related Adverse E vents of Grade 2 or Higher

Reported in More Than 5% of the 87 Study Patients, According to the Dose of P LX4032 Given Tw ice Daily.). A dose of 960 mg twice daily was evaluated and determined to be tolerated in the first six patients given the dose, so it was established as the recommended phase 2 dose for the extension cohort. Those six patients were included as the first six patients in the extension cohort. In the extension cohort, 13 patients (41%) required a dose reduction during therapy (to 720 mg twice daily in 10 patients, to 600 mg twice daily in 1 patient, and to 480 mg twice daily in

2 patients). The most common PLX4032-related grade 2 or

3 side effects observed were arthralgia, rash, nausea, photosensitivity, fatigue, cutaneous squamous-cell carcinoma, pruritus, and palmar–plantar dysesthesia (Table 2). In total, 89% of all side effects were grade 1 or 2. Rashes were evenly distributed among the face or neck, trunk, and extremities.

Eight patients in the dose-escalation cohort (15%) and 10 patients in the extension cohort (31%) had cutaneous squamous-cell carcinomas, with a total of 35 carcinomas. These were reviewed centrally, and all but one either were keratoacanthoma type or had features of a keratoacanthoma. The median time to the appearance of a cutaneous squamous-cell carcinoma was 8 weeks; the majority of the carcinomas were resected, and in no case did they lead to discontinuation of treatment. No squamous-cell carcinomas at other organ sites were observed during the study.

Pharmacokinetics

Pharmacokinetic analyses revealed that exposure increased with the dose throughout the range of doses of the microprecipitated-bulk-powder formulation that were administered, with exposure being proportional to dose for doses of 240 mg twice daily through 960 mg twice daily. At the recommended phase 2 dose, 960 mg twice daily, the mean (±SD) area under the plasma concentration–time curve over a 24-hour period (AUC0–24) was 1741±639

μM×hour (Figure 1A FIGURE 1Mean PLX4032 Concentrations over a 24-Hour Period.), and the mean maximum concentration at steady state was 86±32 μM (Figure 1B). The mean PLX4032 level on day 15, after repeated dosing, was six to nine times the mean level on day 1, and its mean half-life was approximately 50 hours (range, 30 to 80). With the twice-daily dosing regimen, all patients were exposed to relatively constant daily levels of the drug at steady state.

Pharmacodynamics

Tumor-biopsy specimens that had been obtained at baseline and at day 15 were available for seven of the patients in the extension cohort who were receiving PLX4032 at the recommended phase 2 dose. Tumor levels of phosphorylated ERK, cyclin D1, and Ki-67 were markedly reduced at day 15 as compared with baseline in all

specimens tested (Figure 2A FIGURE 2Repr esentative Findings of the E ffect of P LX4032 at the

Recommended Phase 2 Dose in Study P atients w ith Melanoma That Carried the V600E Mutation.). This finding suggests that PLX4032 inhibited the MAP kinase pathway, resulting in decreased cyclin D1 levels and decreased proliferation. In virtually all patients, a marked decrease in tumor uptake of FDG was noted at day 15 (Figure 2B).

Tumor Response

Dose-Escalation Phase

No responses were observed at doses of 160 mg twice daily of the microprecipitated-bulk-powder formulation or at any dose of the crystalline formulation. Of the patients receiving doses of 240 mg or more twice daily, 16 had melanoma with tumors that harbored the V600E BRAF mutation. Among these 16 patients, a partial or complete response was seen in the 1 patient receiving 240 mg twice daily, 2 of the 4 patients receiving 320 or 360 mg twice daily, 4 of the 6 patients receiving 720 mg twice daily, and 4 of the 5 patients receiving 1120 mg twice daily. The overall response rate was 69% (11 of 16 patients), with 10 partial responses and 1 complete response (Fig. 1A in the Supplementary Appendix). Responses were seen at all sites of metastatic disease, including the liver, small bowel, and bone (Figure 2C). The duration of the response ranged from 2 to more than 18 months, with 4 patients still having a partial or complete response at the data cut-off date (Fig. 1B in the Supplementary Appendix). In addition to the patients with melanoma, the 3 patients with papillary thyroid cancer had a partial or complete response, with the response lasting 8 months in 1 patient (who was progression-free for 12 months) and stable disease lasting 11 and 13 months in each of the other 2 patients.

A total of 5 patients with metastatic melanoma whose tumors did not have a BRAF mutation received doses of 240 mg or more twice daily. None had evidence of tumor regression during the study; 4 had progressive disease within the first 2 months of treatment.

Extension Phase

The extension cohort consisted solely of patients who had melanoma with the V600E BRAF mutation. All were treated at the recommended phase 2 dose of 960 mg twice daily. A total of 26 of the 32 patients had a response (81%), with a complete response in 2 patients and a partial response in 24 patients (Figure 3A FIGURE

3Antitumor Response in E ach of the 32 Patients in the Extension Cohort.). Among patients with symptomatic metastatic disease, improvement of symptoms, such as a reduced need for narcotics for pain in 3 patients, was reported within 1 to 2 weeks. As in the dose-escalation cohort, we observed tumor responses in visceral organs and bone metastases as well as more typically responsive sites such as the lungs and lymph nodes. Responses were also routinely observed in patients with elevated lactate dehydrogenase levels (10 partial responses among the 13 patients) and in patients who had received more than one previous type of therapy (11 partial responses among the 16 patients). To date, 16 of the 32 patients are still in the study; the estimated median progression-free survival among these patients is more than 7 months, on the basis of a Kaplan–Meier analysis. The estimated median overall survival has not been reached.

DISCUSSION

Our trial shows that therapy targeting tumors containing activating V600E BRAF mutations can induce complete or partial tumor regression in patients. PLX4032 induced complete or partial tumor regression in 81% of patients who had melanoma with the V600E BRAF mutation. Responses were observed at all sites of disease, including the bone, liver, and small bowel. During the dose-escalation phase of the trial, we also saw responses in patients

who were receiving doses below the recommended phase 2 dose. These efficacy data are particularly encouraging in light of the high disease burden in most of our patients and the presence of symptomatic diseas e in many of them.

Most side effects related to PLX4032 appeared to be proportional to the dose and exposure to the drug. Cutaneous side effects, fatigue, and arthralgia predominated. In the extension cohort, at the dose of 960 mg twice daily, approximately 40% of patients required a short- or long-term reduction in dose to 720 mg, 600 mg, or 480 mg twice daily, many for grade 2 side effects. Squamous-cell carcinoma, keratoacanthoma type, developed in a total of 10 of 32 patients (31%); we also observed squamous-cell carcinoma, keratoacanthoma type, in patients in the dose-escalation cohort. The characteristic rapid eruption of individual, dome-shaped, nonpigmented lesions and histologic findings were present in each case. Usually, squamous-cell carcinoma, keratoacanthoma type, are well-differentiated tumors with very low invasive potential and no metastatic potential; our data do not allow us to determine their behavior in patients receiving PLX4032. Recent data show that BRAF inhibitors can activate the MAP kinase pathway in cells that lack a BRAF mutation.21-23 This activation may pertain to some of the side effects seen with PLX4032.

Though the early response to PLX4032 seems to occur reliably, responsive tumors can develop resistance to treatment. Among the patients in the dose-escalation cohort who had a response to treatment, the duration of the response ranged from 2 to more than 18 months. The mechanism of secondary tumor resistance is not yet known. We also observed that in some patients with V600E BRAF mutations, the tumors showed resistance without evidence of an early response. The mechanism of this primary refractory state is currently under investigation. To date, we have not seen ―gatekeeper‖ BRAF mutations in resistant tumors, although this issue requires more investigation.

Sorafenib, which inhibits BRAF (both the wild type and the V600E mutant) and v-raf-1 murine leukemia viral oncogene homologue 1 (RAF1), has been studied in melanoma. In animal models of melanoma, sorafenib has not shown selective activity against tumors carrying BRAF mutations, and in clinical trials, sorafenib used either alone or in combination with chemotherapy has not had significant antimelanoma effects.24-27 It is possible that the non-BRAF effects of sorafenib mediate side effects that limit the likelihood of achieving a drug concentration that is high enough to inhibit the V600E BRAF mutation.

It is now clear that melanomas can be categorized by specific molecular changes that drive their proliferation.28 The overriding hypothesis is that inhibition of the activated pathway in the individual tumor will lead to tumor regression. There is recent preliminary evidence that imatinib can induce regression in 33% of the small proportion of melanomas driven by mutations in KIT (the v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homologue).29 In our study, PLX4032 induced responses in the vast majority of melanomas caused by BRAF mutations, which constitute 40 to 60% of all melanomas. We do not yet know whether treatment with PLX4032 will improve overall survival; an ongoing phase 3 trial (https://www.sodocs.net/doc/3913843804.html, number, NCT01006980) is addressing that question.

Supported by Plexxikon and Roche Pharmaceuticals.

Drs. Flaherty, Puzanov, Kim, Ribas, McArthur, Sosman, O'Dwyer, and Chapman report the receipt by their institutions of grant support from Plexxikon to conduct this clinical trial; Drs. Flaherty, Puzanov, Kim, Ribas,

Sosman, and Chapman report receiving consulting fees or reimbursement for travel expenses from Roche Pharmaceuticals; Dr. Sosman reports pending receipt of grant support from Roche Pharmaceuticals; Dr. O'Dwyer reports receiving grant support from Plexxikon; Drs. Lee and Grippo report being employees of Roche Pharmaceuticals; and Dr. Nolop reports being an employee of Plexxikon, holding equity in the company, and receiving reimbursement for travel expenses from the company. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at https://www.sodocs.net/doc/3913843804.html,.

SOURCE INFORMATION

From the Abramson Cancer Center of the University of Pennsylvania, Philadelphia (K.T.F., P.J.O.); Massachusetts General Hospital Cancer Center, Boston (K.T.F.); Vanderbilt University, Nashville (I.P., J.A.S.); the University of Texas M.D. Anderson Cancer Center, Houston (K.B.K.); UCLA, Los Angeles (A.R.); Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia (G.A.M.); Roche Pharmaceuticals, Nutley, NJ (R.J.L., J.F.G.); Plexxikon, Berkeley, CA (K.N.); and Memorial Sloan-Kettering Cancer Center, New York (P.B.C.).

Address reprint requests to Dr. Flaherty at Massachusetts General Hospital Cancer Center, 55 Fruit St., Yawkey 9E, Boston, MA 02114, or at kflaherty@https://www.sodocs.net/doc/3913843804.html,.

We thank Drs. Katherine Nathanson and X iaowei X u (of the University of Pennsylvania) for leading the analysis of tumors for BRAF mutations and the immunohistochemical analysis of phosphorylated ERK and Ki-67 during the dose-escalation part of the study, Drs. Astrid Koehler and Michael Stumm (of Roche Pharmaceuticals) for leading these analyses during the extension part of the study, and Dr. Ruben Ayala (of Roche Pharmaceuticals) for the pharmacokinetic analysis.

恶性黑色素瘤治疗(基因突变靶向治疗)

Inhibition of Mutated, Activated BRAF in Metastatic Melanoma Keith T. Flaherty, M.D., Igor Puzanov, M.D., Kevin B. Kim, M.D., Antoni Ribas, M.D., Grant A. McArthur, M.B., B.S., Ph.D., Jeffrey A. Sos man, M.D., Peter J. O'Dw yer, M.D., Richard J. Lee, M.D., Ph.D., Joseph F. Grippo, Ph.D., Keith Nolop, M.D., and Paul B. Chapman, M.D. BACKGROUND The identification of somatic mutations in the gene encoding the serine–threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease. Metastatic melanoma is an aggressive disease for which there are few effective therapies. The two therapies approved by the Food and Drug Administration, high-dose interleukin-2 and dacarbazine, are each associated with response rates of only 10 to 20% and a small percentage of complete responses; neither is thought to improve overall survival.1,2 In randomized trials, the median survival among patients treated with dacarbazine was less than 8 months.3,4 A search for mutations in a component of the mitogen-activated protein (MAP) kinase pathway in a large panel of common cancers revealed that 40 to 60% of melanomas, and 7 to 8% of all cancers, carry an activating mutation in the gene encoding the serine–threonine protein kinase B-RAF (BRAF). 5-15 Ninety percent of reported BRAF mutations result in a substitution of glutamic acid for valine at amino acid 600 (the V600E mutation). This BRAF mutation constitutively activates BRAF and downstream signal transduction in the MAP kinase pathway. BRAF mutations are also found in 40 to 70% of papillary or anaplastic thyroid cancers6-8,16-18 and in a small percentage of several other types of tumor. PLX4032 (Plexxikon; RG7204, Roche Pharmaceuticals) is a potent inhibitor of BRAF with the V600E mutation. Preclinical studies showed that PLX4032 and its analogue PLX4720 inhibit the kinase activity of BRAF with the V600E mutation at low nanomolar concentrations, abrogate signaling through the MAP kinase pathway, and block proliferation of cells carrying BRAF with the V600E mutation in vitro at high nanomolar concentrations.17,18 Orally administered PLX4720 inhibits the growth — and, at higher doses, induces the regression — of human melanoma tumors transplanted into immunocompromised mice. None of these effects are observed in normal tissues or in tumor cells that lack a BRAF mutation. We conducted a trial of the use of PLX4032 in patients with metastatic cancer. The primary goals were to define the safety and pharmacokinetic characteristics of treatment with continuous, twice-daily administration of PLX4032, to determine the maximum dose that could be administered until adverse effects prevented further dose increases (i.e., the recommended phase 2 dose), and to determine the objective response rate, the duration of response, and the rate of progression among patients who had melanoma tumors with the V600E BRAF mutation and who were given the recommended phase 2 dose of PLX4032. METHODS Study Design The study was sponsored by Plexxikon and Roche Pharmaceuticals, which provided the study drug. The study was designed by two academic authors and one industry author. All authors made the decision to submit the

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图1 皮肤镜实现皮肤病变表面下特点可视化。a. 13 mm×7 mm 皮损的临床图片，伴不规则边界及多样色彩。b. 皮肤镜显示带状网格样外观，为黑色素细胞痣诊断特点。c. 5 mm×3 mm 对称的皮损临床图片，中心暗色。d. 皮肤镜显示周边局部伪足，是黑色素瘤特异性皮肤镜标识。插图突出表现了伪足，伪足是瘤体的球状突出物。组织病理学检查证实是原位发生于复合型黑色素细胞痣的黑色素瘤。 数字人体摄影常用于有多量痣和（或）非典型痣患者。照片可用于医务人员的随访检查，以此帮助识别新发或有改变的病损。皮肤镜、连续性数字皮肤镜成像和数字人体摄影通常以互补的方式一起使用。针对高风险黑色素瘤患者的回顾性分析显示结合使用这些技术可早期发现黑色素瘤，并减少良性皮肤病变活检率。 在体反射激光共聚焦显微镜是一种不断发展的非侵入性床旁成像方式，它可使表皮和真皮浅层可视化，分辨率接近组织学清晰度。已证明将此技术作为结合皮肤镜检查的二级诊断测试可改善黑色素瘤诊断的正确率，并减少良性黑色素细胞肿瘤不必要的活检。 检测黑色素瘤的自动诊断系统具有较高的敏感性和特异性，因此引起医务人员和患者的一致好评。过去十年中在美国和欧洲，计算机辅助多光谱数字分析和电化学阻抗谱已处于商业性

黑色素瘤中医保守治疗

黑色素瘤晚期患者的身体状况大都很差，因此只要身体状况允许应尽早进行黑色素瘤晚期治疗，应用抗癌扶正的中医药治疗可快速杀灭癌细胞，缩小肿瘤，控制扩散转移，使症状得以缓解。故黑色素瘤中医保守治疗是很好的选择。下面我们就随专家一起了解下吧。 中医治疗黑色素瘤晚期采用抗癌与扶正固本兼顾的治疗原则，以期控制肿瘤发展，调整机体脏腑功能，提高免疫力，增强体质，改善症状，防止放疔、化疗的副作用和手术后的并发症。中医治疗黑色素瘤晚期在抑制原发癌肿的同时治疗转移癌灶，双管齐下，效果好。 另外，中医中药的整体治疗在扶正固本的治则下彻底铲除病灶，清热解毒，消肿，扶正祛邪，提高患者的免疫力和抗癌能力，达到标本兼治的治疗效果。使病人快速进入康复期，达到延长生命，缓解病痛，提高生存质量，力争使癌症患者生存三年、五年甚至十年以上。 专家介绍，黑色素瘤患者之所以会出现一系列极为痛苦的症状，一方面跟癌肿大范围扩散有关，另一方面也跟治疗带来的副作用有关。只有改善这一情况，才能使治疗顺利进行，并且是减轻黑色素瘤晚期病人痛苦的根本。现在很多医院都是通过中药来治疗黑色素瘤，能够减轻放化疗所带来的毒副作用，提高人体免疫机能，改善症状，减轻黑色素瘤病人的痛苦。用于黑色素瘤的保守治疗的中医药物(三联平衡疗法)副作用小，黑色素瘤的治疗过程中在一定程度上保护患者心、肝、肾等重要脏器的功能，一方面抑制癌细胞增殖，缓解诸多病危症状，另一方面促进患者身体机能的恢复，改善内环境，达到提高患者生存质量，延长生命的目的。 再加上中医治疗黑色素瘤往往价格低廉，比起昂贵的西医治疗，容易被患者接受。选择黑色素瘤中医治疗方法是黑色素瘤患者明智的选择，中医药治疗不仅能够帮助患者减轻病痛的折磨，还能够调养患者的身体，为后续治疗做准备，从而也逐渐解除了患者失去黑色素瘤治疗机会的困扰。 黑色素瘤中医保守治疗——中药三联平衡疗法的治疗优势： 一、组方科学、用药精炼，通过中医独有的清热解毒、扶正祛邪、活血化瘀、软坚化瘤作用迅速封闭癌体的血液循环，切断癌体组织营养供应，加速癌细胞的死亡; 二、破坏或阻止癌细胞的分裂和繁殖，杀灭癌细胞，使瘤体逐渐缩小直至消失; 三、消除"癌性毒性因子"、"癌性疼痛因子"对人体的病理损害，快速减轻病人的痛苦; 四、整体调节阴阳平衡，迅速激活人体的免疫系统，提高机体抵抗力及胃肠消化功能，促进身体康复;

《基因突变和基因重组》习题精选

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中国黑色素瘤诊断治疗共识(2008年第一版)

中国黑色素瘤诊断治疗共识 （2008年第一版） 目录 一、概述 二、流行病学与病因学 三、病理 四、临床病理分期 五、治疗流程及原则 六、辅助治疗 七、手术治疗 八、放疗 九、全身治疗 十、随访 1

一、概述 恶性黑色素瘤(malignant melanoma, MM)是皮肤肿瘤的一种，与鳞癌和基底细胞癌不同。后两种起源于表皮的角质细胞，预后较好。皮肤恶性黑色素瘤是由位于表皮基底部的黑色素细胞恶变形成的，多由痣或色素斑发展而来，一旦进入快速生长期，则预后差、死亡率高。恶性黑色素瘤90%发生于皮肤，最常见于背部，胸腹部和腿部，足底、指趾、甲下、头皮等部位也不少见；少数发生于外阴、消化道和眼内。 早期恶性黑色素瘤经外科扩大切除术后95%-100%可治愈。因此早期发现与早期诊断非常重要。皮肤MM的早期临床表现为痣或色素斑迅速增大，隆起，破溃不愈，边缘不整或有切迹、锯齿，颜色改变、局部形成水泡、瘙痒、刺痛等。进而可出现卫星灶、局部淋巴结肿大，移行转移（原发病灶与区域引流淋巴结之间的皮下结节，通过淋巴管转移）和远处转移1。常见的远处转移部位包括远处皮肤淋巴结、肺、脑、肝、骨等部位，有文献报道仅发生肺转移的预后好于其它远处转移2。 恶性黑色素瘤的预后与性别、年龄、部位、肿瘤厚度、淋巴结转移个数及LDH等相关3。通常来说女性预后好于男性，四肢最好，躯干其次，头颈部预后最差；分期越早预后越好，LDH 越高预后越差。淋巴结有1个转移的5年生存率为75%，有3个转移的为15%；浸润深度<1mm的10年生存率>90%，浸润深度>4.5mm的10年生存率为30%；2008年ASCO会上报道LDH<0.8正常值的患者较LDH高的患者总生存明显延长4。 二、流行病学与病因学：恶性黑色素瘤是所有恶性肿瘤中发病率增长最快的肿瘤，年增长率约3-5%5。英国近5年来MM男性发病率增加了28%，女性增加了12%。据报道美国2007年估计MM 新发病例59940人，死亡约8110人。澳大利亚昆士兰和美国的南亚利桑那州为MM的高发地区，发病率分别为40/10万，30/10万6。白种人发病率高于其他肤色人种。中国和日本等亚洲国家发病率低，但是增长迅猛。北京市八城区统计资料显示2000年恶性黑色素瘤发病率为0.2/10万7，2004年其发病例率已达1/10万。MM平均发病年龄为45岁，50岁以后随年龄 2

中医治疗各个阶段的黑色素瘤

黑色素瘤是对人体皮肤伤害相当严重的一大恶性肿瘤疾病，且黑色素瘤大多是发生在高龄人群中，这一恶性肿瘤不仅转移几率比较高，这就导致患者病情更加严重，因此一旦发现黑色素瘤一定要及时治疗。在治疗黑色素瘤上，中医药治疗黑色素瘤也是比较常见的，下面一起来看一下。 中医作为我国传统的治疗方法，在我国已有数千年的发展历史，不仅治疗理念丰富先进，治疗效果也得到了实践的检验。中医具有很强的整体观念，辩证论治，适合于治疗黑色素瘤的各个阶段。 对于早期黑色素瘤的患者来说，手术虽然能快速切除病灶，控制病情，但是术后的巩固治疗也是不能少的，中医药辅助手术效果效果1+1>2，有效的清除手术及其放化疗后残余的癌细胞及剩余的病灶，预防肿瘤的复发和转移。辅助放化疗治疗能起到增效减毒的作用，帮助患者更好的治疗疾病，提高整体治愈率。单独作用于晚期患者也能起到延长生命，减少患者痛苦的作用。 总之，中医治疗黑色素瘤不仅可以杀伤机体内癌细胞，控制病情恶化，提高患者治愈率。而且中医治疗能够有选择的杀伤癌细胞，副作用非常小，反而还会在治疗过程中调理患者机体，增强机体的免疫力和抵抗力，实现标本兼治的治疗功效，促进患者早日实现康复或长期带瘤生存。 中医治疗黑色素瘤的真实案例： 周某，恶性黑色素瘤，女，河南省濮阳市人。2014年9月份，周某因视力下降在濮阳市油田总医院确诊为黑色素瘤。经过多方打听，慕名来到郑州希福中医肿瘤医院接受袁希福院长的中医治疗。来诊时，患者连手机上的字都看不清，而且怕冷，脚趾疼，时不时就会流血水，脖子上还有一大圈“刺猴”。袁希福根据患者病情，以“三联平衡疗法”为原则为患者开具中药。服药20天后，再次来院时患者向袁希福教授反应：脖子上的刺猴少了3分之2，脚流血流水少了，身上发冷也轻了，现在不碰着不出血!吐痰也轻了，以前疙瘩跟煤炭一样黑!这个疙瘩还可高，现在变薄了不少。看到患者用药情况这么好，袁希福教授嘱咐患者一定要坚持服药。 而以上提到的中医三联平衡疗法是著名的中医肿瘤专家袁希福在传统中医理论及袁氏“阴阳平衡疗法”的基础上，结合30多年临床抗癌实践经验，把传统中医药理论与当代免疫理论、细胞分化增殖周期理论及基因理论等最新医学理

新人教版最新高中基因突变和基因重组教案必修生物

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基因突变与基因重

基因突变与基因重组 【考纲导引】 1.基因重组及其意义Ⅱ 2.基因突变的特征和原因Ⅱ 【考情分析】 1.基因重组的类型、发生的时间、基因突变发生的时间、基因突变和基因重组的区别等都是 不容易掌握的知识，在复习时采用对比的方式，能够化难为易 2.从近几年新课改生物试题看，知识点分布主要集中在基因突变的产生、结果分析与特点的 理解上 3.在命题角度上都与生产生活实际及当前热点密切相关，另外从实验探究与设计的角度考查 考生探究能力的试题也非常多 【基础自测】 （三）基因与性状 ①基因通过控制控制性状，如镰刀型细胞贫血症 基因与性状的关系②基因通过控制控制过程，从而影响生物 性状，如白化病 ③生物的性状是和共同作用的结果 基因突变：概念——指基因的改变，包括的、或原因——根本原因是过程中发生差错 特征①性：在各种生物都可以发生 基因突变②性：自然状况下，基因突变的频率很低 ③性：一种基因突变产生的基因可以再突变为该基因 ④性：一个基因经过突变可以产生不同的等位基因 ⑤性：基因突变可以发生在个体发育的和中 发生时期：基因突变发生在基因时 基因重组种类 可遗传的变异 【要点透析】 基因重组基因突变染色体数量变异（整倍性）多倍体单倍体 发生时期减数第一次分裂细胞分裂间期细胞分裂期某些生物进行单性生殖时 产生机理非同源染色体上 非等位基因的自 DNA上发生碱基对的 增添、缺失、改变， 由于细胞分裂受阻， 体细胞中染色体组成 直接由生物的配 子，如未受精卵细

由组合；交叉互换从而引起DNA碱基序 列即遗传信息的改 变倍的增加胞、花粉粒发育而 来，使染色体组数 成倍减少 是否有新基因产生没有产生新基因， 但产生了新的基 因组合类型 产生了新基因 没有产生新基因，但 增加了某一基因的数 量 没有产生新基因 在生物进化中地位对生物进化有一 定意义 生物变异的主要来 源，提供生物进化的 原始材料 对生物进化有一定意 义 对生物进化的意义 不大 实践应用杂交育种诱变育种多倍体育种单倍体育种 例1自然界中，一种生物某一基因及突变基因决定的蛋白质的部分氨基酸序列如下: 正常基因精氨酸苯丙氨酸亮氨酸苏氨酸脯氨酸 突变基因1 精氨酸苯丙氨酸亮氨酸苏氨酸脯氨酸 突变基因2 精氨酸亮氨酸亮氨酸苏氨酸脯氨酸 突变基因3 精氨酸苯丙氨酸苏氨酸酪氨酸丙氨酸 根据上述氨基酸序列确定这3种突变基因DNA分子的改变是： A．突变基因1和2为一个碱基的替换，突变基因3为一个碱基的增添 B．突变基因2和3为一个碱基的替换，突变基因1为一个碱基的增添 C．突变基因1为一个碱基的替换，突变基因2和3为一个碱基的增添 D．突变基因2为一个碱基的替换，突变基因1和3为一个碱基的增添 考点定位本题主要考察基因突变的类型 指点迷津要解答此题，首先要抓住基因突变的概念。基因突变是指DNA分子中碱基对的增添、缺失或替换。当DNA分子的碱基对增添或缺失时，会使基因的碱基排列顺序从增添或缺失处到最后都发生改变，进而使基因所决定的氨基酸顺序从此处开始都改变；而当DNA分子的个别碱基对替换时，只会影响一个氨基酸的种类（种类可能变，也可能不变），其他的氨基酸则不会改变。据此，分析上述三个突变基因所决定的蛋白质的部分氨基酸序列可知：突变基因1和2为一个碱基的替换，突变基因3为一个碱基的增添。 参考答案 A 例2以下关于生物变异的叙述，正确的是（） A、基因突变都会遗传给后代 B、基因碱基序列发生改变，不一定导致性状改变 C、染色体变异产生的后代都是不育的 D、基因重组只发生在生殖细胞形成过程中 考点定位本题考查的知识点是生物变异的知识。 指点迷津生物的变异的来源有基因突变、基因重组、染色体变异。基因突变是碱基序列发生改变，但由于一种氨基酸可由几种遗传密码与它对应，故不一定导致性状改变。发生在体细胞中的突变一般是不会遗传给后代。应用重组DNA技术，改造的基因，也属于基因重组。有些生物染色体变异时，染色体数目成倍增加，产生的后代就形成了多倍体。