TREATMENT OF BCR/ABL CAUSED LEUKEMIAS WITH FTIs

描述（由申请人提供）：法尼基转移酶抑制剂（FTIs）属于一类相对无毒的新型抗癌药物，目前正在各种癌症的临床试验中进行测试。我们的研究集中在探索用FTIs治疗ph阳性急性淋巴细胞白血病（ALL）的效用。这种类型的白血病是由Bcr/Abl致癌融合蛋白引起的，预后非常不利。在之前的支持期内，我们证明了FTI SCH66336作为单药治疗在转基因小鼠模型中对预防白血病前期进展非常有效，并且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，对这种FTI的耐药性在体外和体内都很容易诱导，我们确定了几种可能有助于这一点的机制。根据我们的初步数据，我们假设，Bcr/Abl淋巴母细胞白血病细胞对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，白血病细胞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疗效，我们提出以下具体目标。(1)探讨ABC转运体的表达和击倒ATP11a在正常和恶性B-lineage细胞和对阻力的影响呢(2)来确定细胞粘附分子表达的影响在前b N-cadherin白血病细胞的能力抵抗治疗呢(3)定义的特点,少数亚种群保护来自成纤维细胞对淋巴母的FTI治疗和随后可以长出来,包括它们对其他药物的敏感性，这些药物的分子靶点可能非常不同。我们的实验将为表达Bcr/Abl的淋巴细胞获得对fti耐药的机制提供重要信息，并将允许更优化地使用这类药物治疗ph阳性ALL，无论是单独治疗还是与其他药物联合使用。fti是一种新型的、迅速发展的、具有较低毒性的抗癌药物。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后会出现的问题非常重要。相关性：对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，这些药物选择性地靶向癌细胞中的特定异常分子，而且相对无毒。为了预测未来这类药物在治疗癌症方面的广泛应用，本项目以急性淋巴细胞白血病和一种药物（FTI）为模型，研究癌细胞如何对这些新药产生耐药性。

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.