Preclinical Development of ACXT-3102 for the Treatment of Pancreatic Adenocarcinoma (PDAC)
ACXT-3102 治疗胰腺癌 (PDAC) 的临床前开发
基本信息
- 批准号:10435565
- 负责人:
- 金额:$ 101.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-23 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AnemiaAntineoplastic AgentsBiological AvailabilityBody WeightCancer Cell GrowthCancer EtiologyCancer ModelCancer PatientCanis familiarisCardiacCardiovascular systemCell DeathCellsCessation of lifeChemicalsClinicalClinical TrialsCystineDataDevelopmentDiseaseDoseDose-LimitingDrug Delivery SystemsDrug KineticsDrug StabilityDrug TargetingEnzymesFatigueFormulationGlutamatesGoalsGrantHalf-LifeHumanIn VitroIncubatedIntravenousInvestigational DrugsLifeLife ExpectancyLigandsMalignant NeoplasmsMalignant neoplasm of pancreasMeasuresMesylatesMetabolicMetabolismMicrosomesModelingMusNo-Observed-Adverse-Effect LevelOralOral AdministrationOxidative StressPaclitaxelPancreasPancreatic AdenocarcinomaPatientsPharmaceutical PreparationsPharmacodynamicsPharmacologyPharmacology StudyPhasePhase I Clinical TrialsPlasmaPlayPractice GuidelinesQuality of lifeRattusRegimenResearchRoleSafetyScheduleSeriesSiteSmall Business Technology Transfer ResearchSodium ChlorideSolidSolubilitySurvival RateTemperatureTestingTherapeuticTherapeutic IndexTimeToxic effectToxicologyTreatment EfficacyTumor VolumeUniversitiesVentricularWashingtonWorkantiporteraqueousbasecancer cellcancer typechemical stabilitycommercial applicationcytotoxicitydesigndrug synthesiseffective therapyerastinfirst-in-humangemcitabinegood laboratory practiceimprovedin vitro Assayin vivomalic enzymemedical schoolsmolecular markermouse modelnerve damagenoveloverexpressionoxaliplatinpancreatic cancer cellspancreatic cancer modelpancreatic cancer patientspharmacokinetics and pharmacodynamicsphysical propertypre-clinicalpreclinical developmentpreclinical studypreventprogramsside effectsigma-2 receptorsmall moleculestandard of caretumortumor growthtumor metabolismuptake
项目摘要
Project Summary/Abstract
Pancreatic cancer is a devastating disease with a very low (8%) 5-year survival rate. Therapeutic options are
limited in efficacy and many have substantial toxicity. Targeted drug delivery may improve the therapeutic
index of cancer drugs by enhancing drug localization to the cancer cell while minimizing off-target side effects.
Sigma-2 receptors (S2R) are highly expressed in pancreatic and other cancers compared to healthy cells.
Accuronix Therapeutics is developing ACXT-3102, a molecule with therapeutic potential licensed from
Washington University School of Medicine in St. Louis (WUSM). ACXT-3102 is comprised of a S2 ligand
covalently bound to the ferroptosis-inducing molecule dm-erastin. Preliminary data show that ACXT-3102
increased the cytotoxicity against pancreatic tumor cells in vitro by 35-fold compared to dm-erastin alone.
ACXT-3102 has tremendous potential as a novel treatment option for pancreatic and perhaps several other
types of cancer. Drug optimization strategies were conducted in a Phase I STTR which resulted in a better
yield during drug synthesis, identification of a mesylate salt with high aqueous solubility and improved physical
properties suitable for oral drug administration, demonstration of good oral efficacy and discovery that tumors
lacking malic enzyme 1 (ME1) are even more sensitive to ACXT-3102.
For this Phase II STTR program, Accuronix Therapeutics will continue to work with our research colleagues
from WUSM to prepare ACXT-3102 for Investigational New Drug (IND) submission and eventually testing the
compound in pancreatic cancer patients. We will conduct a series of preclinical studies to optimize the dosing
regimen in murine pancreatic cancer models – understanding if once, twice or three times per day drug
administration improves plasma exposure and anti-tumor efficacy while maintaining safety, i.e., avoiding dose-
limiting side effects. Studies will also explore if efficacy of our drug can be further improved when given in
combination with gemcitabine, a current standard-of-care for pancreatic cancer. Chemical and metabolic
stability of ACXT-3102 will be established using in vitro assays to guide storage conditions of the drug and
understand which preclinical species best represents metabolism in humans. To obtain data required for the
pharmacology and safety sections of the IND package, preclinical studies will be conducted according to Good
Laboratory Practice (GLP) guidelines to generate pharmacokinetic (PK) and pharmacodynamic (PD) data for
correlating plasma exposures in different species to what is predicted in human. Similarly, formal GLP
toxicology studies will be completed using three different doses in rats and dogs to establish the “No Observed
Adverse Effect Level” (NOAEL). These data will be used to model exposure levels in humans and establish a
safe, first-in-human (FIH) dose for starting our clinical trials in cancer patients. At the conclusion of the Phase
II STTR grant, we will have the pharmacology and safety information on ACXT-3102 required for the IND
package, and will have established the first dose to be used in patients.
项目总结/文摘
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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WILLIAM G HAWKINS其他文献
WILLIAM G HAWKINS的其他文献
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{{ truncateString('WILLIAM G HAWKINS', 18)}}的其他基金
Project 2: Mechanisms of Resistance to Neoantigen Vaccines in PDAC
项目2:PDAC新抗原疫苗耐药机制
- 批准号:
10708575 - 财政年份:2023
- 资助金额:
$ 101.92万 - 项目类别:
Preclinical development of the novel inhibitor of apoptosis proteins S2/IAPinh for cancer therapy
用于癌症治疗的新型凋亡蛋白抑制剂 S2/IAPinh 的临床前开发
- 批准号:
10568409 - 财政年份:2022
- 资助金额:
$ 101.92万 - 项目类别:
Preclinical Development of ACXT-3102 for the Treatment of Pancreatic Adenocarcinoma (PDAC)
ACXT-3102 治疗胰腺癌 (PDAC) 的临床前开发
- 批准号:
10251498 - 财政年份:2019
- 资助金额:
$ 101.92万 - 项目类别:
Washington University SPORE in Pancreatic Cancer
华盛顿大学 SPORE 在胰腺癌中的应用
- 批准号:
9982223 - 财政年份:2016
- 资助金额:
$ 101.92万 - 项目类别:
Washington University SPORE in Pancreatic Cancer
华盛顿大学 SPORE 在胰腺癌中的应用
- 批准号:
9146190 - 财政年份:2016
- 资助金额:
$ 101.92万 - 项目类别:
SIGMA-2/PEPTIDOMIMETIC CONJUGATES TARGET APOPTOSIS IN PANCREATIC CANCER
SIGMA-2/拟肽结合物靶向胰腺癌中的细胞凋亡
- 批准号:
8630870 - 财政年份:2012
- 资助金额:
$ 101.92万 - 项目类别:
SIGMA-2/PEPTIDOMIMETIC CONJUGATES TARGET APOPTOSIS IN PANCREATIC CANCER
SIGMA-2/拟肽结合物靶向胰腺癌中的细胞凋亡
- 批准号:
8219912 - 财政年份:2012
- 资助金额:
$ 101.92万 - 项目类别:
SIGMA-2/PEPTIDOMIMETIC CONJUGATES TARGET APOPTOSIS IN PANCREATIC CANCER
SIGMA-2/拟肽结合物靶向胰腺癌中的细胞凋亡
- 批准号:
8463148 - 财政年份:2012
- 资助金额:
$ 101.92万 - 项目类别:
SIGMA-2/PEPTIDOMIMETIC CONJUGATES TARGET APOPTOSIS IN PANCREATIC CANCER
SIGMA-2/拟肽结合物靶向胰腺癌中的细胞凋亡
- 批准号:
8879063 - 财政年份:2012
- 资助金额:
$ 101.92万 - 项目类别:
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