Targeting CD44-mediated calcium signaling for the treatment of relapsed myeloma

 描述（由申请方提供）：多发性骨髓瘤（MM）是一种恶性肿瘤，最初对标准治疗药物有反应。然而，不幸的是，所有患者都复发了对进一步治疗难治的疾病。我们假设MM的进展和维持需要平衡的CD 44信号传导来控制细胞内Ca 2+池的稳态，因为我们已经证明，第一种内部小分子选择性CD 44激动剂MTI-101引起细胞内Ca 2+水平的毒性增加，从而触发MM细胞坏死。此外，我们已经确定了CD 44下游的关键效应子，这些效应子似乎控制细胞内Ca 2+水平并有助于MTI-101诱导的坏死细胞死亡，特别是内质网（ER）驻留的硫醇氧化还原酶（Ero 1 L）及其靶点Stim 1（ER/质膜（单程）钙传感器）。重要的是，我们还表明：（i）MTI-101对原发性和复发性多发性骨髓瘤都有活性;（ii）MM患者样本中的Ero 1 L表达与对MTI-101的敏感性相关;（iii）Ero 1 L的敲低增加了MM对硼替佐米诱导的细胞死亡的敏感性。在特定目标1中，我们将全面询问原发性骨髓瘤标本（MGUS，新诊断的蛋白酶体抑制剂难治性疾病）中CD 44-Ero 1 L-Stim 1-Ca 2+回路的状态，并将评估MTI-101与其天然配体透明质酸（HA）结合CD 44对细胞内Ca 2+水平和MM细胞存活的影响。我们还将评估原发性和复发性MM中Ero 1 L和Stim 1的水平是否与MTI-101的敏感性、CD 44参与后细胞内Ca 2+池的变化以及对硼替佐米治疗的临床耐药性相关。在特定目标2中，将使用遗传和生化方法评估Ero 1 L和Stim 1在对MTI-101与HA的反应中的调节和作用，以及它们在MTI-101和硼替佐米作为骨髓瘤治疗剂的体内疗效中的作用。最后，在具体目标3中，我们将使用数学模型和验证研究来优化MTI-101的单药和联合治疗。我们提交的拟议研究将建立这种令人兴奋的新药物的作用机制和疗效，该药物靶向原发性和复发性多发性骨髓瘤中的CD 44-Ero 1 L-Stim 1-Ca 2+回路。

 DESCRIPTION (provided by applicant): Multiple Myeloma (MM) is a malignancy that initially responds to standard of care agents. Unfortunately, however, all patients relapse with disease that is refractory to further treatment. We hypothesize that progression and maintenance of MM requires balanced CD44 signaling that controls homeostasis of intracellular Ca2+ pools, as we have shown that a first in class, in-house small molecule selective agonist of CD44 coined MTI-101 provokes toxic increases in the levels of intracellular Ca2+ that trigger MM cell necrosis. Further, we have identified key effectors downstream of CD44 that appear to control intracellular Ca2+ levels and to contribute to MTI-101-induced necrotic cell death, specifically an endoplasmic reticulum (ER) resident thiol oxidoreductase coined Ero1L and its target Stim1, an ER/plasma membrane (single-pass) calcium sensor. Importantly, we have also shown that: (i) MTI-101 has activity against both primary and relapsed multiple myeloma; (ii) Ero1L expression in MM patient samples correlates with sensitivity to MTI-101; and (iii) knockdown of Ero1L augments the sensitivity of MM to bortezomib-induced cell death. In Specific Aim 1 we will fully interrogate the status of the CD44-Ero1L-Stim1-Ca2+ circuit in primary myeloma specimens (MGUS, newly diagnosed and proteasome inhibitor refractory disease) and will assess effects of CD44 engagement by MTI-101 versus its natural ligand hyaluronic acid (HA) on intracellular Ca2+ levels and MM cell survival. We will also evaluate if levels of Ero1L and Stim1 in primary and relapsed MM correlate with sensitivity to MTI-101, with changes in intracellular Ca2+ pools following CD44 engagement, and with clinical resistance to bortezomib treatment. In Specific Aim 2 genetic and biochemical approaches will be used to assess the regulation and roles of Ero1L and Stim1 in the response to MTI-101 versus HA, and their roles in MTI-101 and bortezomib efficacy as therapeutics for myeloma in vivo. Finally, in Specific Aim 3 we will use mathematical models and validation studies to optimize single agent and combination therapy with MTI-101. We submit the proposed studies will establish the mechanism of action and efficacy of this exciting new agent that targets CD44-Ero1L- Stim1-Ca2+ circuit in both primary and relapsed multiple myeloma.