Highly selective targeted theranostics for prostate cancers
前列腺癌的高选择性靶向治疗诊断
基本信息
- 批准号:10468166
- 负责人:
- 金额:$ 64.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-11 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:Adverse eventAffinityAndrogensAnimal ModelAnimalsAntibodiesAntibody-drug conjugatesAntigen TargetingAntigensAntineoplastic AgentsBindingBiochemicalBiological MarkersCancer EtiologyCanis familiarisCarcinomaCell DeathCessation of lifeChemicalsChemoresistanceClinicalClinical TrialsCollectionCombined Modality TherapyCompanionsComplexCytotoxic agentDataDiagnosisDiseaseDoseDrug Delivery SystemsDrug SynergismDrug resistanceDrug toxicityEffectivenessExhibitsFOLH1 geneFutureGenerationsGeneticGoalsHematologic NeoplasmsHormonesHumanImmune responseImmunocompetentImmunologicsImplantLigandsLightLocal TherapyLocalized DiseaseLocationMalignant NeoplasmsMalignant neoplasm of prostateMethodologyMethodsMicrotubulesModificationMolecular WeightMovementMusNormal CellNormal tissue morphologyOperative Surgical ProceduresPUVA PhotochemotherapyPathologyPathway interactionsPatientsPeptidesPharmaceutical PreparationsPhotosensitizing AgentsPhysiologyProdrugsProstate Cancer therapyProstate carcinomaRadiation therapyRadical ProstatectomyReactive Oxygen SpeciesRecurrenceRefractoryRelapseReportingResistanceRiskSiteSolid NeoplasmStructure of base of prostateSystemic TherapyTechnologyTestingTherapeuticTherapeutic EffectTimeTissuesToxic effectToxicologyTranslationsTrastuzumabUnited StatesWeightcancer biomarkerscancer cellcancer heterogeneitycancer therapycell killingchemotherapyclinical applicationclinical efficacyclinical translationcombatcost efficientdesigndisorder riskdrug clearancedrug developmentdrug efficacyefficacy evaluationefficacy studyefficacy trialhigh riskhuman modelhumanized antibodyimprovedirradiationmenminimally invasivemouse modelmultimodalitynovelnovel therapeuticsoverexpressionphthalocyaninepreventprostate cancer modelresponsescreeningserum PSAside effectsmall moleculesystemic toxicitytargeted deliverytargeted imagingtargeted treatmenttheranosticstreatment strategytumorvirtual
项目摘要
Abstract. Prostate cancer (PCa) is the most common malignancy and the second leading cause of cancer
death in men in the United States. Although surgery and radiation therapy in patients with low risk disease appear
appropriate and effective, those with high-risk localized disease almost always become hormone refractory and
then rapidly progress. New treatment strategy is urgently needed for patients with high-risk localized prostate
cancer, particularly an approach that considers the use of a multimodal approach and that includes both local
and systemic therapies.
Cytotoxic drugs are broadly used to treat hematological malignancies and solid tumors and, under certain
clinical conditions, have changed the natural course of some of these diseases. While effective, due to their
intrinsic mode of action, they may also cause significant off-target adverse events that could preclude their full
clinical efficacy, possibly resulting in early discontinuation of medication and a consequent increased risk of
tumor relapse or recurrence. Alternative approaches to both maintain the effectiveness of chemotherapeutic
drugs and minimize systemic toxicity include conjugation of cytotoxic agents to humanized antibodies (also
known as Antibody Drug Conjugates, ADCs). The durable clinical responses reported with brentuximab vedotin
(SGN-35: Seattle Genetics/Takeda) and trastuzumab emtansine (T-DM1; Roche in partnership with
ImmunoGen), which have recently obtained regulatory approval, have profoundly changed the outlook for ADC
cancer therapy. These approaches, although showing strong potential, are extremely expensive, and less
complex and more cost-efficient methodologies are needed.
Here we describe the use of a novel ligand for prostate specific membrane antigen (PSMA, a biomarker
for prostate cancer) to target a potent microtubule inhibiting agent, MMAE, and a photodynamic therapy (PDT)
agent, IR700, selectively to prostate cancers. The design of this new drug molecule utilizes a prodrug approach
and simultaneously delivers two drugs selectively to prostate cancer. By selective delivery of two drugs with
different therapeutic mechanisms to cancer cells, improved antitumor activity with less toxicity is expected. The
reduction in toxicity is expected due to anticipated drug synergy (requiring lower drug doses), site specific
prodrug activation, and rapid clearance of the drug molecule, preventing off target delivery. This molecule will
be developed using two animal models of prostate cancer, heterotopic human prostate cancer in mice and
spontaneous prostate cancer in companion dogs. Both MMAE and IR700 therapy have been noted to stimulate
immune response against cancer and we will preliminarily tested this in the immunocompetent companion dogs.
Dog pathology and physiology of prostate cancer is very similar to humans and dogs are often used in
drug development trials. Since efficacy trials in mice are not predictive of human results, efficacy studies in dogs
will substantially encourage clinical translation of the developed agent.
抽象的。前列腺癌是最常见的恶性肿瘤,也是第二大致癌原因。
美国男性死亡人数。尽管手术和放射治疗在低风险疾病患者中出现
适当和有效,那些有高风险局部疾病的人几乎总是变得激素抵抗和
然后迅速进步。高危局限性前列腺患者迫切需要新的治疗策略
癌症,尤其是一种考虑使用多模式方法的方法,包括局部和局部
和系统性治疗。
细胞毒性药物被广泛用于治疗血液系统恶性肿瘤和实体肿瘤,在某些情况下
临床情况,改变了其中一些疾病的自然病程。虽然有效,但由于他们的
固有的行动模式,它们还可能引起重大的非目标不良事件,从而可能阻止其完全
临床疗效,可能导致提前停药,从而增加发病风险
肿瘤复发或复发。两种维持化疗效果的替代方法
药物和最大限度地减少全身毒性包括将细胞毒剂与人源化抗体(也
称为抗体药物结合物(ADC)。布妥昔单抗的持久临床疗效报告
(SGN-35:西雅图遗传学/武田)和曲妥珠单抗emtansine(T-DM1;罗氏与
最近获得了监管部门的批准,这深刻地改变了ADC的前景
癌症治疗。这些方法虽然显示出很大的潜力,但非常昂贵,而且成本更低
需要复杂和更具成本效益的方法。
在这里,我们描述了一种新的前列腺特异性膜抗原(PSMA)配体的用途,PSMA是一种生物标记物
用于前列腺癌)靶向一种有效的微管抑制剂MMAE和光动力疗法(PDT)
试剂IR700选择性地治疗前列腺癌。这种新药分子的设计利用了前药的方法。
同时选择性地提供两种治疗前列腺癌的药物。通过选择性地给药两种药物
针对肿瘤细胞不同的治疗机制,有望在提高抗肿瘤活性的同时降低毒副作用。这个
由于预期的药物协同作用(需要较低的药物剂量),预计毒性将会降低,具体地点
前药激活,并快速清除药物分子,防止偏离目标给药。这个分子会
使用两种前列腺癌动物模型,小鼠异位人前列腺癌和
伴犬的自发性前列腺癌。已经注意到MMAE和IR700疗法都能刺激
对癌症的免疫反应,我们将在免疫能力强的伴犬身上初步测试这一点。
狗的前列腺癌的病理和生理学与人类非常相似,狗经常被用在
药物开发试验。由于在小鼠身上进行的疗效试验不能预测人类的效果,所以在狗身上进行的功效研究
将极大地鼓励已开发试剂的临床翻译。
项目成果
期刊论文数量(0)
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James Peter Basilion其他文献
James Peter Basilion的其他文献
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{{ truncateString('James Peter Basilion', 18)}}的其他基金
Highly selective targeted theranostics for prostate cancers
前列腺癌的高选择性靶向治疗诊断
- 批准号:
10674499 - 财政年份:2021
- 资助金额:
$ 64.59万 - 项目类别:
Highly selective targeted theranostics for prostate cancers
前列腺癌的高选择性靶向治疗诊断
- 批准号:
10296947 - 财政年份:2021
- 资助金额:
$ 64.59万 - 项目类别:
Fluorescence-guided resection of breast tumors using a topically-applied molecular probe
使用局部应用分子探针进行荧光引导乳腺肿瘤切除术
- 批准号:
10543808 - 财政年份:2020
- 资助金额:
$ 64.59万 - 项目类别:
Fluorescence-guided resection of breast tumors using a topically-applied molecular probe
使用局部应用分子探针进行荧光引导乳腺肿瘤切除术
- 批准号:
9891289 - 财政年份:2020
- 资助金额:
$ 64.59万 - 项目类别:
Fluorescence-guided resection of breast tumors using a topically-applied molecular probe
使用局部应用分子探针进行荧光引导乳腺肿瘤切除术
- 批准号:
10322725 - 财政年份:2020
- 资助金额:
$ 64.59万 - 项目类别:
Improved Detection of Prostate Cancer with Nanoparticle-based Ultrasound Contrast Agents Targeted to PSMA
使用针对 PSMA 的纳米颗粒超声造影剂改进前列腺癌的检测
- 批准号:
10067372 - 财政年份:2017
- 资助金额:
$ 64.59万 - 项目类别:
Theranostic gold nanoparticles for imaged-guided radical prostatectomy and PDT ablation
用于影像引导根治性前列腺切除术和 PDT 消融的治疗诊断金纳米颗粒
- 批准号:
9207085 - 财政年份:2016
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Dual-Receptor Targeted Nanoparticles for Photodynamic Therapy of Brain Cancer
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8304224 - 财政年份:2010
- 资助金额:
$ 64.59万 - 项目类别:
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