Mechanisms of resistance to cancer therapeutics

描述(申请人提供)：在大约75%的转移性乳腺癌患者中，骨骼是转移的首选部位。HH信号通路在乳腺癌中异常激活。我们的实验室已经研究了Hedgehog(HH)通路作为乳腺癌骨转移的决定因素的作用。我们观察到了乳腺癌细胞、成骨细胞和破骨细胞之间通过HH通路产生的一种新的串扰，该通路导致骨吸收。我们进一步注意到，抑制乳腺癌细胞中的HH信号导致注射乳腺癌细胞的裸鼠股骨和胫骨中的肿瘤生物量减少。骨骼是一种低氧微环境(PO2在1-7%之间)。在低氧条件下，细胞从有氧代谢转变为无氧代谢，以满足生存所需的能量需求。因此，肿瘤缺氧选择依赖于无氧代谢的细胞。这增加了肿瘤生物量，包括适应在低氧条件下存活的转移性肿瘤细胞(注：无氧代谢不同于Warburg效应，后者是有氧糖酵解)。我们的目标是(I)评估低氧诱导乳腺癌细胞对HH抑制剂耐药的机制(S)和(Ii)确定阻断HH抑制剂的治疗益处。 乳腺癌细胞的低氧反应增强其对HH抑制剂的敏感性我们假设，骨骼中的低氧环境以及随之而来的乳腺癌细胞的低氧反应激活了肿瘤细胞中的非经典HH信号，使其对HH抑制剂产生抗药性。我们的假设将在以下特定目标描述的研究中得到验证：特定目标1：阐明HH信号影响乳腺癌细胞适应缺氧(厌氧代谢)和诱导骨溶解能力的机制(S)。具体目的2：明确缺氧诱导HH信号非经典激活的机制(S)，并确定其对乳腺癌细胞溶骨活性的影响。具体目标3：确定克服HH信号和缺氧骨微环境的影响以预防乳腺癌溶骨性转移的临床前治疗益处。预期结果：缺氧骨微环境可能选择HH信号异常激活的肿瘤细胞，这些肿瘤细胞依赖于缺氧骨环境来维持其生存。我们将在临床前模型中对百时美施贵宝的药物HH抑制剂与HIF-1抑制剂联合使用的治疗益处进行评分。影响：我们预计，我们的工作将激励和指导乳腺癌I/II期临床试验的设计，以确定使用HH和缺氧抑制剂的联合治疗方案在预防和/或治疗乳腺癌溶骨性转移方面的临床有效性。

DESCRIPTION (provided by applicant): In about 75 percent of metastatic breast cancer patients, bone is the preferred site for metastasis. The Hh signaling pathway is aberrantly activated in breast cancer. Our laboratory has investigated the role of the Hedgehog (Hh) pathway as a determinant of metastasis of breast cancer to the bone. We have observed a novel crosstalk between breast cancer cells, osteoblasts and osteoclasts via the Hh pathway that results in bone resorption. We further noted that inhibition of Hh signaling in breast cancer cells resulted in decreased tumor biomass in the femur and tibia of athymic mice injected with breast cancer cells. Bone is a hypoxic microenvironment (pO2 between 1-7%). Under hypoxia, cells switch from aerobic to anaerobic metabolism to meet the energy requirements for survival. Thus, tumor hypoxia selects for cells dependent on anaerobic metabolism. This increases the tumor biomass comprising of metastatic tumor cells adapted for survival under hypoxic conditions (Note: Anaerobic metabolism is distinct from the Warburg effect, which is aerobic glycolysis). Our objective is (i) to evaluate the mechanism(s) of hypoxia-induced resistance of breast cancer cells to Hh inhibitors and, (ii) to establish the therapeutic benefit of impeding the hypoxia response of breast cancer cells to enhance their sensitivity to Hh inhibitors We hypothesize that the hypoxic environment in the bone and the consequent hypoxic response of breast cancer cells activates non-classical Hh signaling in the tumor cells making them resistant to Hh inhibitors. Our hypothesis will be tested in studies described in the following SPECIFIC AIMS: Specific Aim 1: Elucidate the mechanism(s) by which Hh signaling impacts the ability of breast cancer cells to adapt to hypoxia (anaerobic metabolism) and induce osteolysis. Specific Aim 2: Define the mechanism(s) of hypoxia-induced non-classical activation of Hh signaling and determine its impact on osteolytic activity of breast cancer cells. Specific Aim 3: Determine the pre-clinical therapeutic benefit of overcoming the impact of Hh signaling and the hypoxic bone microenvironment to prevent osteolytic metastases of breast cancer. Expected outcome: The hypoxic bone microenvironment may select for tumor cells with aberrantly activated Hh signaling that are addicted to the hypoxic bone milieu for their sustenance. We will score the therapeutic benefit of combining a pharmacologic Hh inhibitor from Bristol-Myers Squibb in conjunction with a HIF-1¿ inhibitor, in a pre-clinical model. Impact: We anticipate that our work will motivate and guide the design of a Phase I/II clinical trial for breast cancer to determine th clinical effectiveness of a combined treatment regimen using Hh and hypoxia inhibitors in preventing and/or treating breast cancer osteolytic metastasis.