Combining Immune Therapy with Targeted Therapies to Improve Melanoma Survival
免疫治疗与靶向治疗相结合以提高黑色素瘤的生存率
基本信息
- 批准号:10265337
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-10-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:American Society of Clinical OncologyAntibodiesBRAF geneBindingCDK4 geneCDKN2A geneCTLA4 geneCell CycleChromosome 7Chromosome 8Clinical TrialsColorectal CancerCytogeneticsDiseaseDisease regressionDysmyelopoietic SyndromesEffectivenessExhibitsGene MutationGene TargetingGenesGrantGrowthHumanImmune responseImmunocompetentImmunotherapyLactate DehydrogenaseLeadLeukocytesLifeLow-Density LipoproteinsMAP Kinase GeneMEKsMalignant NeoplasmsMalignant neoplasm of lungMetastatic MelanomaModelingMonosomyMutateMutationMyocarditisNF1 mutationNeoplasm MetastasisNivolumabPLK1 genePathway interactionsPatientsPhosphotransferasesProgression-Free SurvivalsProteinsProto-Oncogene Proteins c-aktRas/RafReportingResearchResearch Project GrantsResistanceResistance developmentSafetySerious Adverse EventSignal PathwaySignal TransductionSiteStable DiseaseT cell responseT-LymphocyteTherapeuticTimeTransgenic ModelTrisomyVeteransXenograft procedureanti-CTLA4anti-PD-1anti-PD-L1 therapyanti-PD1 therapybasecancer celleffectiveness evaluationfightinghumanized mouseimprovedinhibitor/antagonistipilimumabkinase inhibitormeetingsmelanomamouse modelmutantneoplastic cellpancreatic cancer modelpatient derived xenograft modelphase 3 studyprogrammed cell death protein 1recruitresponseside effectsmall molecule inhibitorstandard of caresuccesstargeted treatmenttumortumor growth
项目摘要
ABSTRACT:
Metastatic melanoma is one of the fastest growing tumor types in the US, one of the top 5
cancers among Veterans, and is also one of the most challenging malignancies to treat. Currently
immune therapies targeting the check-point inhibitors such as CTLA-4 and/or PD-1 can enhance the T
cell response to tumor an these inhibitors have shown great success and as a result have moved to
first line standard of care for most metastatic melanoma patients. Ipilimumab (targeting CTLA-4)
combined with nivolumab (targeting PD-1) has yielded a 59% response rate in melanoma patients.
Melanoma patients with an increased mutational load, and those with NF1 mutation, respond better to
anti-PD1 or anti-PDL1 therapy. However, side effects are often extensive, producing severe adverse
events in >60% of patients including myocarditis for combined anti-CTLA4 and anti-PD1 therapy.
Clearly, refinements of current treatments are needed to enhance survival of metastatic melanoma
patients. Approximately 40% of melanoma tumors have mutation or loss of CDKN2A. One of the
genes encoded by CDKN2A, INK4a is important for inhibiting the cell cycle kinases, CDK4/6. This
results in loss of restrictions on cell cycle and enhanced proliferation of melanoma tumor cells. We
have shown that inhibitors of the cell cycle kinases, CDK4/6, can both slow the growth of some
melanoma tumors and also enhance T cell recruitment into the tumors. Moreover, approximately 80%
of melanoma patients have activating mutations in the RAS/RAF/MEK/MAPK pathway (30% with
mutation in NRAS and 51% with mutation of BRAF). Another 23% have alterations resulting in
activation of the PI3K pathway. Recently rigosertib (RGS), a non-ATP competitive multi-kinase
inhibitor, has been shown to inhibit the RAS/RAF/MEK and PI3K signaling pathways which are also
crucial for melanoma tumor growth. We propose here to determine the effectiveness of combining
CDK4/6 inhibitors with RGS in comparison to anti-PD1 therapy which is standard of care. We
hypothesize that RGS, which targets multiple kinases, will be effective for treating RAS mutant
melanoma in combination with CDK4/6 inhibitors. We also propose that an even greater response will
occur when check point inhibitors such as anti- PD1 or with activating antibody to CD137 are added to
the RGS and CDK4/6i combined therapy regime. In this research grant we will examine the ability of
CDK4/6 inhibitor combined with RGS to inhibit the growth of melanoma in immune competent mouse
models of melanoma, including NRAS mutant, BRAF mutant, and B16 melanoma (WT for NRAS and
BRAF). We will also examine the effects of CDK4/6 inhibition combined with RGS on the immune
response to the tumor and characterize the effectiveness of combining RGS with anti-PD1 or other
check point inhibitors, or with addition of anti-CD137 treatment in immune competent mouse models
of melanoma. Finally, we will evaluate the effectiveness of combining CDK4/6 inhibitor and RGS with
anti-PD1 or anti-CD137 for treatment of melanoma patient derived xenografts using humanized
mouse models. This study should lead to new and improved therapeutic options for treating our
Veterans with metastatic melanoma.
摘要:
转移性黑色素瘤是美国增长最快的肿瘤类型之一,
癌症的退伍军人,也是最具挑战性的恶性肿瘤治疗之一。
靶向检查点抑制剂如CTLA-4和/或PD-1的免疫疗法可以增强T细胞
细胞对肿瘤的反应,这些抑制剂已经显示出巨大的成功,因此已经转移到
大多数转移性黑色素瘤患者的一线标准治疗。伊匹单抗(靶向CTLA-4)
与nivolumab(靶向PD-1)联合使用,在黑色素瘤患者中产生了59%的应答率。
突变负荷增加的黑色素瘤患者和NF 1突变的黑色素瘤患者对以下治疗的反应更好:
抗PD 1或抗PDL 1治疗。然而,副作用往往是广泛的,产生严重的不良反应,
抗CTLA 4和抗PD 1联合治疗可使>60%的患者发生包括心肌炎在内的不良事件。
显然,需要改进当前的治疗方法以提高转移性黑色素瘤的生存率
患者大约40%的黑色素瘤肿瘤具有CDKN 2A的突变或缺失。之一
由CDKN 2A编码的基因INK 4a对于抑制细胞周期激酶CDK 4/6是重要的。这
导致对细胞周期的限制丧失和黑素瘤肿瘤细胞的增殖增强。我们
已经表明,细胞周期激酶CDK 4/6的抑制剂可以减缓一些细胞的生长,
黑色素瘤肿瘤,还增强T细胞募集到肿瘤中。此外,约80%
的黑色素瘤患者在RAS/RAF/MEK/MAPK通路中存在激活突变(30%,
NRAS突变和51% BRAF突变)。另外23%的人有改变,
PI 3 K通路的激活。最近,rigosertib(RGS),一种非ATP竞争性多激酶
抑制剂,已显示抑制RAS/RAF/MEK和PI 3 K信号传导途径,其也是
对黑色素瘤的生长至关重要我们建议在这里确定结合的有效性
CDK 4/6抑制剂与RGS相比,抗PD 1治疗是标准治疗。我们
假设靶向多种激酶RGS将有效治疗RAS突变
黑色素瘤与CDK 4/6抑制剂的组合。我们还建议,
当添加检查点抑制剂如抗PD 1或CD 137活化抗体时,
RGS和CDK 4/6 i联合治疗方案。在这项研究补助金中,我们将检查
CDK 4/6抑制剂联合RGS抑制免疫活性小鼠黑色素瘤生长
黑色素瘤模型,包括NRAS突变体、BRAF突变体和B16黑色素瘤(NRAS和B16黑色素瘤的WT)。
BRAF)。我们还将研究CDK 4/6抑制与RGS联合对免疫系统的影响。
对肿瘤的反应,并表征RGS与抗PD 1或其他抗PD 1抗体组合的有效性。
检查点抑制剂,或在免疫活性小鼠模型中添加抗CD 137治疗
黑色素瘤最后,我们将评估CDK 4/6抑制剂和RGS联合治疗的有效性,
使用人源化的抗PD 1或抗CD 137治疗黑素瘤患者来源的异种移植物
小鼠模型。这项研究将为治疗我们的糖尿病提供新的和改进的治疗选择。
患有转移性黑色素瘤的退伍军人。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Ann Richmond其他文献
Ann Richmond的其他文献
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{{ truncateString('Ann Richmond', 18)}}的其他基金
BLR&D Merit Review Research Career Scientist (RCS) Award (IK6)
BLR
- 批准号:
10618231 - 财政年份:2020
- 资助金额:
-- - 项目类别:
BLR&D Merit Review Research Career Scientist (RCS) Award (IK6)
BLR
- 批准号:
10454101 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Optimizing Response to Immune Checkpoint Inhibitor Therapy for Breast Cancer: A Role for Inhibitors of the PI3K pathway
优化乳腺癌免疫检查点抑制剂治疗的反应:PI3K 通路抑制剂的作用
- 批准号:
10305634 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Optimizing Response to Immune Checkpoint Inhibitor Therapy for Breast Cancer: A Role for Inhibitors of the PI3K pathway
优化乳腺癌免疫检查点抑制剂治疗的反应:PI3K 通路抑制剂的作用
- 批准号:
9916443 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Optimizing Response to Immune Checkpoint Inhibitor Therapy for Breast Cancer: A Role for Inhibitors of the PI3K pathway
优化乳腺癌免疫检查点抑制剂治疗的反应:PI3K 通路抑制剂的作用
- 批准号:
10531596 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Combining Immune Therapy with Targeted Therapies to Improve Melanoma Survival
免疫治疗与靶向治疗相结合以提高黑色素瘤的生存率
- 批准号:
10609814 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Combining Immune Therapy with Targeted Therapies to Improve Melanoma Survival
免疫治疗与靶向治疗相结合以提高黑色素瘤的生存率
- 批准号:
10369756 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Modeling New Therapeutic Approaches for Malignant Melanoma
模拟恶性黑色素瘤的新治疗方法
- 批准号:
8817140 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Modeling New Therapeutic Approaches for Malignant Melanoma
模拟恶性黑色素瘤的新治疗方法
- 批准号:
8633274 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Modeling New Therapeutic Approaches for Malignant Melanoma
模拟恶性黑色素瘤的新治疗方法
- 批准号:
8966669 - 财政年份:2013
- 资助金额:
-- - 项目类别:
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