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.
文摘:
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(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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