Control of lethal prostate cancer with a bispecific av and a5b1 integrin antibody

摘要 全世界每年死于前列腺癌的30万人中，大部分都与骨骼有关 转移，因为在大多数晚期男性中，骨骼是临床疾病的唯一部位 生病了。我们对支撑高效和生命的机制的认识存在着根本性的差距- 前列腺癌细胞对骨骼微环境的威胁定植。我们的长期目标是 基于对骨骼病理生理学的分子理解开发新的治疗策略 从而显著提高前列腺癌患者的生存率和生活质量。我们的 实验室研究发现前列腺癌细胞表达两种不同但功能相关的整合素 它们的归宿、生存和致命性在骨骼微环境中传播。这项研究的基本原理是 同时针对这两种整合素的双特异性抗体将通过其 交联的作用机制，并提供有效的治疗策略。因此，一流的 针对这些整合素的双特异性抗体显示出更好的抗肿瘤活性 单特异性抗体单独或组合使用。一种独特的双特异性作用分子机制 对抗体进行了定义。在使用一种或两种单特异性整合素抗体治疗后，适应性 整合素上调，而与之相反，整合素在双特异性之后下调 通过诱导整合素的内化和溶酶体降解进行抗体治疗。我们的假设是 双特异性整合素抗体将阻止危及生命的骨内前列腺癌的进展 微环境。我们计划用三个具体目标来评估这一假说。首先，我们计划评估 双特异性抗体与单特异性抗体在不同骨动物模型中的疗效比较 复制临床疾病关键维度的转移：骨髓播种，与 人骨来源的基质细胞，加速生长和从骨中二次传播，最后， 成骨细胞表型的产生。其次，我们将进一步明确政府的作用机制 双特异性整合素抗体对上皮-间充质转化、失巢凋亡和细胞凋亡的影响 克隆生存。最后，我们将通过以下方式确定这两种整合素表达的器官特异性 比较这些整合素在前列腺癌和其他实体肿瘤骨转移中的表达 在淋巴结和内脏器官发现的转移。我们的创新治疗策略使 前列腺癌侵袭骨微环境的分子机制很重要，因为 它有可能显著延长前列腺癌患者的生存时间，提高患者的生活质量。 在骨骼中定居的实体肿瘤，如乳腺癌，可能利用相同的分子途径，扩大 双特异性抗体策略在生物标记物支持的临床试验中的潜在意义和影响 跟着。

ABSTRACT The majority of the 300,000 annual deaths worldwide from prostate cancer are strongly attributed to bone metastasis because the skeleton is the exclusive site of clinical disease in the majority of men with advanced illness. There is a fundamental gap in our knowledge of the mechanisms that underpin the efficient and life- threatening colonization of the bone microenvironment by prostate cancer cells. Our long-term goal is to develop novel therapeutic strategies based on a molecular understanding of the pathophysiology of bone metastases in order to significantly improve survival and quality of life outcomes in prostate cancer. Our laboratory studies implicate two different but functionally related integrins expressed by prostate cancer cells in their homing, survival and lethal spread within the bone microenvironment. The rationale of this study is that a bispecific antibody that simultaneously targets these 2 integrins would optimally neutralize their function via its cross-linking mechanism of action and deliver an efficacious therapeutic strategy. Accordingly, a first-in-class bispecific antibody targeting these integrins demonstrated superior antitumor activity compared to monospecific antibodies alone or in combination. A distinct molecular mechanism of action for the bispecific antibody was defined. Following treatment with either or both monospecific integrin antibodies, adaptive upregulation of the integrins was seen whereas by contrast, downregulation of integrins followed bispecific antibody treatment via induction of internalization and lysosomal degradation of integrins. Our hypothesis is that the bispecific integrin antibody will halt the life-threatening progression of prostate cancer in the bone microenvironment. We plan to evaluate this hypothesis with three specific aims. First, we plan to assess the efficacy of the bispecific antibody compared to monospecific antibodies in distinct animal models of bone metastases that replicate key dimensions of the clinical disease: seeding of the bone marrow, interaction with human bone-derived stromal cells, accelerated growth and secondary dissemination from bone, and finally, generation of an osteoblastic phenotype. Secondly, we will further define the mechanism of action of the bispecific integrin antibody by assessing its impact on epithelial-mesenchymal transition, anoikis and clonogenic survival. Finally, we will determine the organ-specificity of the expression of the two integrins by comparing the expression of these integrins in bone metastases from prostate cancer and other solid tumors to metastases found in lymph nodes and visceral organs. Our innovative therapeutic strategy to disable the molecular mechanisms of colonization of the bone microenvironment by prostate cancer is significant because it has the potential to significantly prolong survival and improve quality of life of patients with prostate cancer. Solid tumors that colonize bone such as breast cancer may leverage the same molecular pathways, expanding the potential significance and impact of the bispecific antibody strategy in biomarker-supported clinical trials to follow.