Modulation of cancer induced immune suppression via inhibition of SCD1
通过抑制 SCD1 调节癌症诱导的免疫抑制
基本信息
- 批准号:10546697
- 负责人:
- 金额:$ 40万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcidsAdjuvant TherapyAffectAnabolismAnalytical ChemistryApoptoticBiological AvailabilityBiological MarkersBladderBreastCancer ModelCancer cell lineCanis familiarisCell DeathCell LineCell ProliferationCell SurvivalCell physiologyChemoresistanceClinical TrialsClinical Trials DesignColonCombined Modality TherapyDataDiseaseDoseDrug FormulationsDrug KineticsDrug resistanceERBB2 geneEnzymesEssential Fatty AcidsFatty AcidsFood and Drug Administration Drug ApprovalFormulationGenerationsGrantHumanImmuneImmune checkpoint inhibitorImmune responseImmunityImmunocompetentImmunologyImmunosuppressionImmunotherapyInfiltrationInflammatoryInvestigational DrugsInvestigational New Drug ApplicationKidneyLeadLinkLiverMalignant NeoplasmsMalignant neoplasm of pancreasMaximum Tolerated DoseMeasuresMediatingMediator of activation proteinMelanoma CellMembraneMetabolicMonounsaturated Fatty AcidsMusNo-Observed-Adverse-Effect LevelNutrientOncogenicOralOvarianPD-1 inhibitorsPathway interactionsPatientsPharmacology and ToxicologyPhasePhase I Clinical TrialsPhase III Clinical TrialsPhenotypePlayPrincipal InvestigatorPropertyProteinsReportingRoleSaturated Fatty AcidsSignal TransductionSiteSmall Business Innovation Research GrantSmall Interfering RNASolid NeoplasmStearoyl-CoA DesaturaseSynthesis ChemistryT-LymphocyteTherapeuticThyroid GlandToxic effectToxicologyTranslationsTumor-infiltrating immune cellsadaptive immune responseadaptive immunityantagonistanti-PD1 antibodiesanti-PD1 therapyanti-cancerantitumor effectarmattenuationbasecalreticulincancer cellcancer immunotherapycancer typecapsulecarcinogenesiscell killingclinical practicecombatcomputational chemistrydeprivationdesignearly phase clinical trialendoplasmic reticulum stressfatty acid biosynthesisfatty acid metabolismfirst-in-humanimmune activationimmune checkpoint blockadeimmunogenicimmunogenicityin vivoinhibitorinsightlipid biosynthesislipid metabolismmalignant breast neoplasmmouse modelneoplastic cellnovelnovel strategiesnovel therapeutic interventionoverexpressionpatient responsepatient stratificationphase I trialpredictive markerrefractory cancerresponseresponse biomarkersmall moleculesynergismtargeted treatmenttherapeutic targettherapeutically effectivetherapy resistanttriple-negative invasive breast carcinomatumortumor microenvironmenttumorigenic
项目摘要
PROJECT SUMMARY
Metabolic reprogramming plays a critical role in carcinogenesis, in part due its ability to promote immune
suppressive properties within tumors. It remains unclear whether inhibition of fatty acid metabolism in tumors
affects their immunogenicity. We show that inhibition of stearoyl CoA desaturase 1 (SCD1), the rate limiting
enzyme involved in fatty-acid synthesis converting saturated acids (SFA) to monounsaturated fatty acids
(MUFAs), increases the immunogenicity of poorly immunogenic tumors. Our results indicate that inhibition of
tumorigenic de novo lipogenesis represents a novel approach to enhance T cell-based cancer
immunotherapy. In so doing, our novel lead SCD1 inhibitor (MTI-301; aka SSI-4) singly, and in combination with
immune checkpoint inhibitors (ICIs) using immune competent mouse models demonstrates anti-tumor synergy
sensitizing tumors to ICIs, as a prelude to an early phase clinical trial. We will also optimize efficacy and seek
predictive biomarkers of response that could be useful for the design and stratification of patients in the critical
Phase III clinical trial. SCD1 is universally upregulated in aggressive cancers and validated by MTI-301 antitumor
activity across a broad range of cancer cell lines and tumor mouse models. Mechanistically, MUFA deprivation
in addicted cancer cells leads to endoplasmic reticulum (ER) stress mediating apoptotic cell death. We
discovered using immune competent mouse cancer models that MTI-301 activates the adaptive immune
response via calreticulin/PERK arm of the ER stress pathway enhancing activated T cell tumor infiltration and
thereby promoting anti-PD1 antibody therapy. Combined with anti-PD1 inhibitor, MTI-301 sensitizes tumors to
immune checkpoint inhibitors in mouse triple negative breast cancer (TNBC) and HER2 breast cancer mouse
models. Based upon these data, our central hypothesis is that aberrant de novo lipogenesis is linked to
attenuation of tumor immunogenicity. Three aims are proposed in this fast-track Phase 1/2 SBIR proposal. In
Aim 1 (Milestone 1, Phase I SBIR), GLP dog toxicology study will be completed to identify the No-observed-
adverse-effect level (NOAEL) enabling calculation of the first in human dose for the phase I clinical trial. In Aim
2 (Milestone 2, Phase II SBIR), GMP MTI-301 will be synthesized and capsulated along with submission of the
investigation of new drug (IND) application for FDA Phase I trial approval. In Aim 3 (Milestone 3, Phase II SBIR),
a Phase I clinical trial will be performed and exploratory biomarkers including identification of immune infiltrates
into the tumor site will be assessed. In summary, we envision SCD1 as a broad-spectrum anti-cancer target
overexpressed in aggressive malignancies. Therapeutically useful, MTI-301 increases the immunogenicity of
poorly immunogenic tumors thereby sensitizing to immune checkpoint blockade, leading to dramatic adaptive
immune mediated tumor cell killing. This combination therapy should enhance patient response rates and be
well tolerated in patients.
项目摘要
代谢重编程在肿瘤发生中起着关键作用,部分原因是它能够促进免疫反应,
肿瘤内的抑制特性。目前尚不清楚抑制肿瘤中的脂肪酸代谢是否
影响其免疫原性。我们发现,抑制硬脂酰辅酶A去饱和酶1(SCD 1),
参与脂肪酸合成的酶,将饱和酸(SFA)转化为单不饱和脂肪酸
MUFA增加了免疫原性差的肿瘤的免疫原性。我们的研究结果表明,
致瘤性从头脂肪生成代表了一种新的方法,以提高T细胞为基础的癌症
免疫疗法。在此过程中,我们的新型先导SCD 1抑制剂(MTI-301; aka SSI-4)单独使用,以及与
使用免疫活性小鼠模型的免疫检查点抑制剂(ICI)显示出抗肿瘤协同作用
使肿瘤对ICI敏感,作为早期临床试验的前奏。我们还将优化疗效,
反应的预测性生物标志物,可用于设计和分层的患者在关键的
III期临床试验。SCD 1在侵袭性癌症中普遍上调,并通过MTI-301抗肿瘤药物验证
在广泛的癌细胞系和肿瘤小鼠模型中的活性。机械性地剥夺MUFA
在上瘾的癌细胞中,导致内质网(ER)应激介导凋亡性细胞死亡。我们
使用免疫活性小鼠癌症模型发现,MTI-301激活适应性免疫
通过ER应激途径的钙网蛋白/PERK臂的应答增强活化的T细胞肿瘤浸润,
从而促进抗PD 1抗体治疗。MTI-301与抗PD 1抑制剂联合使用可使肿瘤对
小鼠三阴性乳腺癌(TNBC)和HER 2乳腺癌小鼠中的免疫检查点抑制剂
模型基于这些数据,我们的中心假设是异常的新生脂肪生成与以下因素有关:
肿瘤免疫原性的减弱。在这份快速通道第1/2阶段SBIR提案中提出了三个目标。在
目标1(里程碑1,I期SBIR),将完成GLP犬毒理学研究,以确定未观察到的-
副作用水平(NOAEL),能够计算I期临床试验的首次人体剂量。在Aim中
2(里程碑2,第II阶段SBIR),GMP MTI-301将沿着提交的
新药(IND)申请FDA I期试验批准的调查。在目标3(里程碑3,第二阶段SBIR)中,
将进行I期临床试验,探索性生物标志物,包括免疫浸润的鉴定
将评估肿瘤部位。总之,我们设想SCD 1作为广谱抗癌靶点,
在侵袭性恶性肿瘤中过度表达。在治疗上有用的是,MTI-301增加了免疫原性。
免疫原性差的肿瘤,从而对免疫检查点阻断敏感,导致显著的适应性免疫缺陷。
免疫介导的肿瘤细胞杀伤。这种联合治疗应该提高患者的反应率,
患者耐受良好。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John A. Copland其他文献
1022: Transforming Growth Factor β Type 3 Receptor is a Tumor Suppressor Gene in Conventional Renal Cell Carcinoma
- DOI:
10.1016/s0022-5347(18)38259-4 - 发表时间:
2004-04-01 - 期刊:
- 影响因子:
- 作者:
John A. Copland;Tapaty Maity;Shauna LeGrand;Pheroze Tamboli;Joanna Taormina;Christopher G. Wood - 通讯作者:
Christopher G. Wood
PET imaging of differentiated thyroid cancer with thyrotropin-alfa
- DOI:
10.1038/s41598-025-94923-0 - 发表时间:
2025-04-03 - 期刊:
- 影响因子:3.900
- 作者:
Grayson R. Gimblet;Pratheek Reddy;Michelle M. Holland;Hailey A. Houson;Jason Whitt;John A. Copland;Saad S. Kenderian;Renata Jaskula-Sztul;Suzanne E. Lapi - 通讯作者:
Suzanne E. Lapi
John A. Copland的其他文献
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{{ truncateString('John A. Copland', 18)}}的其他基金
Modulation of cancer induced immune suppression via inhibition of SCD1
通过抑制 SCD1 调节癌症诱导的免疫抑制
- 批准号:
10896572 - 财政年份:2022
- 资助金额:
$ 40万 - 项目类别:
Engineered microtumor arrays for development of combination therapies
用于开发联合疗法的工程微肿瘤阵列
- 批准号:
10029690 - 财政年份:2020
- 资助金额:
$ 40万 - 项目类别:
Engineered microtumor arrays for development of combination therapies
用于开发联合疗法的工程微肿瘤阵列
- 批准号:
10442587 - 财政年份:2020
- 资助金额:
$ 40万 - 项目类别:
Engineered microtumor arrays for development of combination therapies
用于开发联合疗法的工程微肿瘤阵列
- 批准号:
10667422 - 财政年份:2020
- 资助金额:
$ 40万 - 项目类别:
Engineered microtumor arrays for development of combination therapies
用于开发联合疗法的工程微肿瘤阵列
- 批准号:
10259730 - 财政年份:2020
- 资助金额:
$ 40万 - 项目类别:
Osteopontin-targeted therapy for primary CNS lymphoma
原发性中枢神经系统淋巴瘤的骨桥蛋白靶向治疗
- 批准号:
9342631 - 财政年份:2017
- 资助金额:
$ 40万 - 项目类别:
Novel SCD1 inhibitors for treatment of cancer
用于治疗癌症的新型 SCD1 抑制剂
- 批准号:
9768370 - 财政年份:2016
- 资助金额:
$ 40万 - 项目类别:
Novel SCD1 inhibitors for treatment of cancer
用于治疗癌症的新型 SCD1 抑制剂
- 批准号:
9048181 - 财政年份:2016
- 资助金额:
$ 40万 - 项目类别:
RhoB in cancer pathogenesis and as a target in combinatorial therapy
RhoB 在癌症发病机制中的作用及其作为组合治疗的靶点
- 批准号:
8458908 - 财政年份:2010
- 资助金额:
$ 40万 - 项目类别:
RhoB in cancer pathogenesis and as a target in combinatorial therapy
RhoB 在癌症发病机制中的作用及其作为组合治疗的靶点
- 批准号:
8080445 - 财政年份:2010
- 资助金额:
$ 40万 - 项目类别:
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