Mechanisms of resistance to cancer therapeutics

描述（由申请人提供）：在大约75%的转移性乳腺癌患者中，骨是转移的首选部位。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。我们观察到乳腺癌细胞、成骨细胞和破骨细胞之间通过Hh通路产生新的串扰，从而导致骨吸收。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胸腺小鼠股骨和胫骨的肿瘤生物量减少。骨是一个缺氧微环境（pO2在1-7%之间）。在缺氧条件下，细胞从有氧代谢转变为无氧代谢，以满足生存所需的能量。因此，肿瘤缺氧选择依赖于无氧代谢的细胞。这增加了由转移性肿瘤细胞组成的适应于缺氧条件下生存的肿瘤生物量（注意：无氧代谢不同于Warburg效应，后者是有氧糖酵解）。我们的目标是(1)评估缺氧诱导乳腺癌细胞对Hh抑制剂耐药的机制，(2)确定阻断Hh抑制剂的治疗益处

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.