Disrupting Brain Metastogenesis in Breast Cancer

描述（由申请人提供）：患有乳腺癌的妇女发生脑转移后预后很差，很少有人能长期生存。这些患者的临床结果在过去几十年中没有显著改善，原因有很多，包括大多数抗癌药物穿过血脑屏障的渗透性差，在绝大多数实验性治疗剂的临床试验中特别排除了脑转移患者，以及对原发性乳腺肿瘤向脑转移所涉及的生物化学和分子事件的不完全理解。自噬是一种进化上保守的蛋白质降解的溶酶体系统，用于长寿命蛋白质和细胞器的周转。最近的一些研究 已经表明，自噬在癌症发病机制中起重要作用，因为它可以起到提供代谢燃料的来源的作用，以维持细胞在应激条件下的存活，包括由缺氧和抗癌治疗引发的那些。我们和其他人已经表明，自噬显着有助于耐药性，因此，抑制这种降解途径显着增强了多种癌症治疗的疗效，并干扰疾病进展。然而，其机制基础尚未完全阐明，自噬在乳腺癌转移调节中的具体作用及其作为转移性疾病预防和治疗靶点的意义尚未得到严格研究。我们的初步数据表明，原发性乳腺肿瘤转移到脑可能需要功能性自噬途径，这表明靶向自噬可能是预防和治疗转移性脑肿瘤的有效方法。我们最近发现了一种新的自噬抑制剂，它很容易穿过血脑屏障，具有显著的抗肿瘤活性，因此是一种非常有前途的治疗原发性和转移性乳腺肿瘤的新候选药物。我们假设自噬的遗传或药理学抑制将拮抗乳腺癌进展，破坏脑中转移性肿瘤的建立，并显著增强小分子EGFR/HER 2抑制剂拉帕替尼的疗效。在目标1中，我们将研究自噬在原发性和转移性乳腺肿瘤的发展和进展中的具体作用。在目标2中，我们将确定自噬抑制增强拉帕替尼治疗乳腺癌的抗脑转移活性的机制。在这些研究的结论中，我们将大大扩展我们关于自噬在乳腺癌发病机制中的作用的知识，并将产生开发新策略所需的关键新信息，以最佳靶向脑转移用于治疗乳腺癌和其他恶性肿瘤。

DESCRIPTION (provided by applicant): Women with breast cancer who develop brain metastases have a dismal prognosis and very few achieve long- term survival. Clinical outcomes for these patients have not significantly improved over the last several decades for a number of reasons including the poor penetration of most anticancer drugs across the blood- brain barrier, the specific exclusion of patients with brain metastases from the vast majority of clinical trials of experimental therapeutic agents, and an incomplete understanding of the biochemical and molecular events that are involved in the metastasis of primary breast tumors to the brain. Autophagy is an evolutionarily conserved lysosomal system of protein degradation that is utilized for the turnover of long-lived proteins and organelles. A number of recent studies have shown that autophagy plays an important role in cancer pathogenesis as it can function to provide a source of metabolic fuel to maintain cell survival under stressful conditions including those triggered by hypoxia and anticancer therapy. We and others have shown that autophagy significantly contributes to drug resistance and accordingly, that inhibiting this degradation pathway significantly augments the efficacy of multiple classes of cancer therapeutics and interferes with disease progression. However, the mechanistic basis for this has not been fully elucidated and the specific role that autophagy plays in the regulation of breast cancer metastasis nor its significance as a target for the prevention and therapy of metastatic disease has not been rigorously investigated. Our preliminary data indicate that a functional autophagy pathway may be required for primary breast tumors to metastasize to the brain, suggesting that targeting autophagy may be an effective approach to prevent and treat metastatic brain tumors. We recently discovered a novel inhibitor of autophagy that readily crosses the blood-brain barrier, has significant anti-neoplastic activity, and is therefore a very promising new candidate drug for the treatment of both primary and metastatic breast tumors. We hypothesize that genetic or pharmacological inhibition of autophagy will antagonize breast cancer progression, disrupt the establishment of metastatic tumors in the brain, and significantly augment the efficacy of the small molecule EGFR/HER2 inhibitor lapatinib. In Aim 1, we will investigate the specific roles that autophagy plays in the development and progression of primary and metastatic breast tumors. In Aim 2, we will determine the mechanism(s) by which autophagy inhibition enhances the anti-brain metastatic activity of lapatinib for the treatment of breast cancer. At the conclusion of these studies, we will have significantly expanded our knowledge regarding the role of autophagy in breast cancer pathogenesis and will have generated critical new information required to develop novel strategies to optimally target brain metastases for the treatment of breast cancer and other malignancies.