Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma

Abstract

In ovarian cancer patients, tumor fibrosis and angiotensin-driven fibrogenic signaling have been shown to inversely correlate with survival. We sought to enhance drug delivery and therapeutic efficacy by remodeling the dense extracellular matrix in two orthotopic human ovarian carcinoma xenograft models. We hypothesized that targeting the angiotensin signaling axis with losartan, an approved angiotensin system inhibitor, could reduce extracellular matrix content and the associated “solid stress,” leading to better anticancer therapeutic effect. We report here four translatable findings: (i) losartan treatment enhances the efficacy of paclitaxel—a drug used for ovarian cancer treatment—via normalizing the tumor microenvironment, resulting in improved vessel perfusion and drug delivery; (ii) losartan depletes matrix via inducing antifibrotic miRNAs that should be tested as candidate biomarkers of response or resistance to chemotherapy; (iii) although losartan therapy alone does not reduce tumor burden, it reduces both the incidence and the amount of ascites formed; and (iv) our retrospective analysis revealed that patients receiving angiotensin system inhibitors concurrently with standard treatment for ovarian cancer exhibited 30 mo longer overall survival compared with patients on other antihypertensives. Our findings provide the rationale and supporting data for a clinical trial on combined losartan and chemotherapy in ovarian cancer patients.

Combining microenvironment normalization strategies to improve cancer immunotherapy

“…Indeed, our previous studies (24)(25)(26) showed that inhibiting CXCL12/CXCR4 or angiotensin signaling can target cancer-associated fibroblasts (CAFs) and extracellular collagen and hyaluronan, which in turn alleviates intratumoral forces, decompresses tumor vessels, and improves perfusion as well as the outcome of ICBs. We have referred to this approach as stroma normalization (27)(28)(29)(30).…”

Flow-induced Shear Stress Confers Resistance to Carboplatin in an Adherent Three-Dimensional Model for Ovarian Cancer: A Role for EGFR-Targeted Photoimmunotherapy Informed by Physical Stress

“…Approximately one-third of all ovarian cancer patients will develop ascites, but this number can be as high as nearly 90% [99] in patients with advanced-stage disease (stages III or IV). The presence and progression of ascites are associated with grim survival statistics, a decreased quality of life, and may have predictive value for malignant ovarian tumors [3,5,11,[14][15][16][17]26,31,[99][100][101][102]. The predictive value of ascites remains a source of debate, as is the case with most clinical and biological markers for this challenging disease [98,[103][104][105].…”

“…Malignant ascites provide fluid-based routes for exfoliated tumor clusters and cells to spread throughout the peritoneum, as well as a nutrient-and chemokine-rich environment to promote the growth and motility of cancer cells [3][4][5]. Establishment of metastatic colonies in the peritoneum has a significant negative impact on survival outcomes and makes the disease exceptionally difficult to treat, with frequent recurrence [2,8,9,[11][12][13][14]. Studies have shown that ascites contribute to tumor heterogeneity, modulate the expression of integrins, and alter the activity of matrix-degrading enzymes in ovarian cancer [5,11,[15][16][17].…”

Rapid stromal remodeling by short‐term VEGFR2 inhibition increases chemotherapy delivery in esophagogastric adenocarcinoma

“…However, they propose that these effects are mediated by treatment‐induced tumor hypoxia while our experimental setup revealed that CAFs play a key role in this process. Zhao and colleagues reveal that inhibition of angiotensin II receptor type I with losartan normalizes the tumor stroma and improves drug delivery (Zhao et al , ). Interestingly, Smith and colleagues describe that the specific architecture of the tumor stroma defines the tumor response to anti‐angiogenic therapies.…”