TREATMENT OF BCR/ABL CAUSED LEUKEMIAS WITH FTIs

描述(申请人提供)：法尼基转移酶抑制剂(FTI)属于一类相对无毒的新型抗癌药物，目前正在对各种癌症进行临床试验。我们的研究重点是探索FTIs治疗Ph阳性急性淋巴细胞白血病(ALL)的有效性。这种类型的白血病是由bcr/abl癌基因融合蛋白引起的，预后非常差。在之前的支持期间，我们证明了FTI SCH66336作为单一疗法在转基因小鼠模型中防止白血病前期进展非常有效，并可以显著延长疾病进展和肿瘤负担非常高的小鼠的寿命。然而，在体外和体内都可以很容易地诱导对这种FTI的耐药性，我们发现了几种可能导致这种耐药的机制。根据我们的初步数据，我们假设，BCR/Abl淋巴细胞白血病细胞对FTI SCH66336的耐药性的发展是由白血病细胞微环境之间的相互作用促进的，该微环境选择了能够在药物限制条件下存活的假定白血病干细胞亚群。为了研究这一点，并提高FTI治疗根除恶性细胞的效率，我们提出了以下具体目标。(1)探讨ABC转运蛋白ATP11a在正常和恶性B系细胞中的表达和敲除及其对FTI耐药性的影响(2)确定细胞黏附分子N-钙粘素在B前B期白血病细胞中的表达对其抵抗FTI治疗能力的影响(3)确定少数淋巴母细胞亚群的特征，包括它们对其他药物的敏感性，这些淋巴母细胞亚群可以通过FTI治疗获得保护并随后能够生长出来，包括它们对其他药物的敏感性。我们的实验将为表达bcr/abl的淋巴母细胞对FTIs产生耐药性的机制提供重要信息，并将允许这类药物更优化地用于Ph阳性ALL的治疗，无论是作为单一治疗还是与其他药物联合使用。FTIs是一类毒性相对较低、发展迅速、前景广阔的新型抗癌药物。正因为如此，我们的研究对于预测这些类型的药物在大量人类患者身上使用时会出现的问题非常重要。相关性：对于接受化疗的患者来说，一个主要问题是他们的癌细胞经常对药物治疗停止反应。在过去的5年里，新型抗癌药物有了惊人的发展，这种药物选择性地针对癌细胞中特定的异常分子，而且相对无毒。考虑到未来此类药物将被广泛用于治疗癌症，该项目使用急性淋巴细胞白血病和一种药物(FTI)作为模型，研究癌细胞如何对这些新药产生抗药性。

DESCRIPTION (provided by applicant): Farnesyltransferase inhibitors (FTIs) belong to a novel class of relatively non-toxic anti-cancer drugs that are currently being tested in clinical trials for a variety of cancers. Our studies have focused on exploring the utility of treating Ph-positive acute lymphoblastic leukemia (ALL) with FTIs. This type of leukemia is caused by the Bcr/Abl oncogenic fusion protein and has a very unfavorable prognosis. In the previous period of support, we showed that the FTI SCH66336 as monotherapy is extremely effective in preventing progression of pre-leukemia in a transgenic mouse model and can significantly prolong the life of mice with progressed disease and a very high tumor burden. However, drug resistance against this FTI could be readily induced both in vitro and in vivo and we identified several mechanisms that can contribute to this. Based on our preliminary data, we hypothesize, that the development of resistance of Bcr/Abl lymphoblastic leukemia cells to the FTI SCH66336 is facilitated by interactions between the microenvironment of the leukemic cells, which selects out a subpopulation of putative leukemia stem cells that is able to survive under the drug-restrictive conditions. To investigate this and to increase the efficacy of eradicating the malignant cells with FTI treatment, we propose the following Specific Aims. (1) To explore the expression and knockdown of the ABC transporter ATP11a in normal and malignant B-lineage cells and the effect of this on resistance to FTIs (2) To determine the effect of expression of the cell adhesion molecule N-cadherin in pre-B leukemia cells on their ability to resist treatment with FTIs (3) To define the characteristics of the minority subpopulations of lymphoblasts that derive protection from fibroblasts against FTI treatment and subsequently are able to grow out, including their sensitivity to other drugs with a presumed very different molecular target. Our experiments will provide important information on the mechanisms by which the Bcr/Abl expressing lymphoblasts acquire resistance to FTIs and will allow for a more optimal use of this class of drugs in the treatment of Ph-positive ALL, either as monotherapy or in combination with other drugs. FTIs belong to a novel, rapidly expanding class of promising anti-cancer drugs with relatively low toxicity. Because of this, our studies are very important in anticipating the problems that will emerge once these types of drugs are used on large numbers of human patients. Relevance: A major problem for patients who are treated with chemotherapy is that their cancer cells frequently stop responding to drug treatment. In the past 5 years there has been a spectacular development of new types of anti-cancer drugs that selectively target specific abnormal molecules in the cancer cells and that are relatively non-toxic. In anticipation of the future widespread use of such drugs to treat cancer, this project examines how cancer cells may develop resistance against these new drugs, using acute lymphoblastic leukemia and a drug (an FTI) as model.