Preclinical Studies on Polyunsaturated Fatty Acid-Taxoid Conjugate for IND Filing

用于 IND 申报的多不饱和脂肪酸-紫杉烷偶联物的临床前研究

• 批准号: 8058152
• 负责人: RAMESH CHANDER GUPTA
• 金额: $ 65.6万
• 依托单位: CHEM-MASTER INTERNATIONAL, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-10 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058152
• 关键词: Preclinical; Studies; Polyunsaturated; Fatty; Acid

DESCRIPTION (provided by applicant): An unmet need in the area of cytotoxic therapy for human cancer is the development of an agent that is highly effective, yet is relatively safe with respect to side effects. The use of most chemotherapeutic drugs in human cancer treatment is accompanied by a variety of side effects including hair loss, corrugated and twisted nail formation and hemorrhage of the mucosa of the alimentary canal. The attractive aspects of DHA-SBT-1214 are its ability to target tumor cells then, once absorbed, release the cytotoxic taxoid moiety where it will do the most damage. This is the innovative aspect of this drug development program. Such a drug should readily find a place in the armamentarium of anti-tumor drug substances. With minimal side effects, it should also lend itself commercially to combination therapy in conjunction with an anti-tumor enzyme regulator, as is becoming the common practice in modern cancer treatment. Chem-Master's mission is to develop DHA-SB-T-1214 as efficacious and safer drug for cancer chemotherapy, especially against tumors that cannot effectively be treated by Taxol(R), docetaxel, Taxoprexin(R), and other commonly used chemotherapeutic drugs. In the SBIR Phase I study, we have made significant progress toward this goal. We have confirmed that the chemical synthesis of DHA-SBT-1214 with high purity is feasible at 10 g scale based on the proposed synthetic route. We have also confirmed the remarkable efficacy of DHA- SBT-1214 against pancreatic cancer (CFPAC-1) and non-small cell lung cancer (H460) xenografts in SCID mice models in addition to highly drug-resistant (Pgp+) colon cancer (DLD-1) xenograft as well as significant activity against another highly drug-resistant (Pgp+) breast cancer (LCC6-MDR) xenograft, wherein Taxol(R) and Taxoprexin(R) showed very limited activity or totally inactive. The project proposed in this Phase II application is designed to advance our studies on DHA-SBT-1214 to treat a variety of human tumors principally associated with colon, breast, lung and pancreatic cancers as well as to perform pre-clinical toxicology studies required for IDN filing and approval. Thus, the key technical objectives in the Phase II studies are (i) further expansion of the current studies to cancer cell lines that are more refractory to other cytotoxic agents and/or to faster growing tumors; (ii) Pharmacokinetics/pharmacodynamics (PK/PD) studies including half-life, distribution, metabolism and maximum tolerated dose, as well as all other pre-clinical toxicology studies necessary for IND filing; (iii) optimization of the preparative methods in 200 g scale for the reliable production of DHA-SBT-1214 in GMP and the development of validation methods for the various intermediates in the synthetic sequence. PUBLIC HEALTH RELEVANCE: The proposed project is of great relevance to human health. Currently there are no really effective drug substances that can abolish or even partially inhibit the growth of human colon cancer because this particular form of cancer over-expresses the MDR phenotype. Remarkably DHA-SBT-1214, an omega-3 fatty acid- taxoid conjugate, can penetrate these cancer cells selectively and by-pass the MDR apparatus, thereafter inducing cell death. The further development of DHA-SBT-1214 as a possible treatment for colon, pancreatic, lung, breast and other forms of cancer could scarcely be more relevant in a society where many forms of this multi-variate and largely untreatable disease, seem to be increasing.

描述（由申请人提供）：人类癌症细胞毒性治疗领域的一个未满足的需求是开发一种高度有效但副作用相对安全的药物。在人类癌症治疗中使用大多数化学治疗药物伴随着各种副作用，包括脱发、波纹和扭曲的指甲形成以及消化道粘膜出血。DHA-SBT-1214的吸引人的方面是其靶向肿瘤细胞的能力，然后一旦被吸收，释放细胞毒性紫杉烷部分，在那里它将造成最大的损害。这是该药物开发计划的创新方面。这样的药物应该很容易在抗肿瘤药物物质的设备中找到位置。由于副作用最小，它也应该在商业上适合与抗肿瘤酶调节剂结合的联合治疗，这正在成为现代癌症治疗中的常见做法。Chem-Master的使命是开发DHA-SB-T-1214作为有效和安全的癌症化疗药物，特别是针对Taxol（R），多西他赛，Taxoprexin（R）和其他常用化疗药物不能有效治疗的肿瘤。在SBIR I期研究中，我们已经朝着这一目标取得了重大进展。我们已经证实，化学合成的DHA-SBT-1214具有高纯度，在10 g规模的基础上，提出的合成路线是可行的。我们还证实了DHA-SBT-1214在SCID小鼠模型中对胰腺癌（CFPAC-1）和非小细胞肺癌（H460）异种移植物以及对高度耐药（Pgp+）结肠癌（DLD-1）异种移植物的显著功效，以及对另一种高度耐药（Pgp+）乳腺癌的显著活性（LCC 6-MDR）异种移植物，其中Taxol（R）和Taxoprexin（R）显示出非常有限的活性或完全无活性。本II期申请中提出的项目旨在推进我们对DHA-SBT-1214的研究，以治疗主要与结肠癌、乳腺癌、肺癌和胰腺癌相关的各种人类肿瘤，并进行IDN申报和批准所需的临床前毒理学研究。因此，II期研究的关键技术目标是（i）将当前研究进一步扩展至对其他细胞毒性药物和/或生长更快的肿瘤更难治的癌细胞系;（ii）药代动力学/药效学（PK/PD）研究，包括半衰期、分布、代谢和最大耐受剂量，以及IND申报所需的所有其他临床前毒理学研究;（iii）优化200 g规模的制备方法，以便在GMP中可靠地生产DHA-SBT-1214，并开发合成序列中各种中间体的验证方法。 公共卫生相关性：拟议项目与人类健康密切相关。目前还没有真正有效的药物可以消除或甚至部分抑制人结肠癌的生长，因为这种特定形式的癌症过度表达MDR表型。值得注意的是，DHA-SBT-1214，一种ω-3脂肪酸-紫杉烷缀合物，可以选择性地穿透这些癌细胞并绕过MDR装置，然后诱导细胞死亡。DHA-SBT-1214作为结肠癌、胰腺癌、肺癌、乳腺癌和其他形式癌症的可能治疗方法的进一步发展，在这种多变量且基本上无法治疗的疾病的许多形式似乎正在增加的社会中几乎没有更相关的意义。