Ceramide Nanoliposomes in Combination with Focused Ultrasound for Treating Breast Cancer

三阴性乳腺癌构成了一个持续的临床挑战，因为它是难治性的， 可用的内分泌或靶向治疗。事实上，患者的预后是暗淡的，因为中位时间较短， 与其他乳腺癌亚型相比，复发和死亡。总的来说，我们的团队正在努力开发 针对该患者群体的改进的治疗方案。我们建议通过将两个独立的 治疗方式[即神经酰胺纳米脂质体（CNL）和图像引导聚焦超声（FUS）] 消融/加热]将提供治疗协同作用。我们期望CNL和 FUS基于以下证据：（i）它们都能够减少，可能通过不同的机制， 肿瘤微环境中的免疫抑制和（ii）全身施用的脂质体的递送 在FUS靶向肿瘤中显著增强。 该提案包括两个具体目标。目标1是确定哪种FUS方案（亚消融 加热或部分热消融）最有效地增强神经酰胺纳米脂质体的治疗功效 对抗乳腺癌FUS将与CNL联合应用于4 T1（三阴性）乳腺肿瘤 局最有效的FUS方案的确定将基于肿瘤生长和 动物生存数据。切除的肿瘤的质谱将确定FUS是否增强神经酰胺 交付.我们还将对肿瘤组织、肿瘤引流淋巴液进行全面的免疫学分析， 淋巴结（LN）、非引流LN、脾和血液。目标2将是调查是否最 FUS和CNL的治疗有效组合与毒性相关。我们将重复最 目的1的有效FUS+CNL组合，并评估毒性（肝和心肌酶，心脏/神经和 肺生理参数和血液学和免疫学标记物）。最后，我们将表演 检查FUS应用是否影响CNL化学的离体研究。展望未来，请注意，Co-PI Kester已经成功收到了FDA的IND（IND 109487），以启动1期试验。如果 如果拟议的研究取得成功，我们机构将继续进行CNL和FUS的后续1/2期试验。

Triple negative breast cancer poses a persistent clinical challenge given that it is refractory to most available endocrine or targeted therapies. Indeed, patient prognosis is dim in light of shorter median time to relapse and death compared to other breast cancer subtypes. Broadly speaking, our group is working to develop an improved therapy regimen for this patient population. We propose to achieve this by combining 2 separate treatment modalities [i.e. ceramide nanoliposomses (CNL) and image-guided focused ultrasound (FUS) ablation/heating] that we postulate will offer therapeutic synergy. Our expectation of synergy between CNL and FUS is based on evidence that (i) they are both capable of reducing, perhaps through distinct mechanisms, immunosuppression in the tumor microenvironment and (ii) the delivery of systemically administered liposomes is markedly enhanced in FUS-targeted tumors. The proposal consists of 2 specific aims. Aim 1 will be to determine which FUS regime (sub-ablative heating or partial thermal ablation) most effectively enhances the treatment efficacy of ceramide nanoliposomes against breast cancer. FUS will be applied to 4T1 (triple negative) breast tumors in combination with CNL administration. Determination of the most efficacious FUS regime will be made based upon tumor growth and animal survival data. Mass spectrometry of excised tumors will ascertain whether FUS enhances ceramide delivery. We will also perform comprehensive immunological analyses on tumor tissue, tumor draining lymph nodes (LNs), non-draining LN, spleen, and blood. Aim 2 will then be to investigate whether the most therapeutically efficacious combination of FUS and CNL is associated with toxicity. We will repeat the most efficacious FUS+CNL combination from Aim 1 and assess toxicity (liver and cardiac enzymes, cardio/neural and pulmonary physiological parameters, and hematological and immunological markers). Finally, we will perform ex-vivo studies to examine whether FUS application affects CNL chemistry. Going forward, note that Co-PI Kester has already successfully received an IND from the FDA (IND 109487) to initiate a phase 1 trial. If the proposed studies are successful, a follow-on phase 1/2 trial with CNL and FUS would ensue at our institution.