Chemotherapy forms the backbone of current treatments for many patients with advanced non-small-cell lung cancer (NSCLC). However, the survival rate is low in these patients due to the development of drug resistance, including cisplatin resistance. In this study, we developed a novel strategy to combat the growth of cisplatin-resistant (CR) NSCLC cells. We have shown that treatment with the plant-derived, non-psychotropic small molecular weight molecule, cannabidiol (CBD), significantly induced apoptosis of CR NSCLC cells. In addition, CBD treatment significantly reduced tumor progression and metastasis in a mouse xenograft model and suppressed cancer stem cell properties. Further mechanistic studies demonstrated the ability of CBD to inhibit the growth of CR cell lines by reducing NRF-2 and enhancing the generation of reactive oxygen species (ROS). Moreover, we show that CBD acts through Transient Receptor Potential Vanilloid-2 (TRPV2) to induce apoptosis, where TRPV2 is expressed on human lung adenocarcinoma tumors. High expression of TRPV2 correlates with better overall survival of lung cancer patients. Our findings identify CBD as a novel therapeutic agent targeting TRPV2 to inhibit the growth and metastasis of this aggressive cisplatin-resistant phenotype in NSCLC.

Recent studies have demonstrated that racial differences can influence breast cancer incidence and survival rate. African American (AA) women are at two to three fold higher risk for breast cancer than other ethnic groups. AA women with aggressive breast cancers show worse prognoses and higher mortality rates relative to Caucasian (CA) women. Over the last few years, effective treatment strategies have reduced mortality from breast cancer. Unfortunately, the breast cancer mortality rate among AA women remains higher compared to their CA counterparts. The focus of this review is to underscore the racial differences and differential regulation/expression of genetic signatures in CA and AA women with breast cancer. Moreover, immune cell infiltration significantly affects the clinical outcome of breast cancer. Here, we have reviewed recent findings on immune cell recruitment in the tumor microenvironment (TME) and documented its association with breast cancer racial disparity. In addition, we have extensively discussed the role of cytokines, chemokines, and other cell signaling molecules among AA and CA breast cancer patients. Furthermore, we have also reviewed the distinct genetic and epigenetic changes in AA and CA patients. Overall, this review article encompasses various molecular and cellular factors associated with breast cancer disparity that affects mortality and clinical outcome.

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer associated with a poor prognosis. However, there have been few advancements in improving the survival of SCLC patients in recent decades. This study shows that the S100A9 protein is highly expressed in SCLC patients and several highly aggressive SCLC cell lines. Furthermore, we showed that S100A9 expression inversely correlates with overall survival in SCLC patients. S100A9 increases the survival and migration of SCLC cells by activating Akt and GSK3α/β/Snail pathways. In addition, S100A9 reduces tumor cell autophagy through MAGE-A3. S100A9 depletion or pharmacological inhibition using tasquinimod reduced tumor growth and metastasis in vivo. Importantly, we observed that S100A9 downregulation or tasquinimod treatment alone or combined with cisplatin reduces the recruitment of MDSCs. Furthermore, tasquinimod treatment alone or combined with cisplatin significantly enhanced tumor infiltration of activated CD8+ (CD69-positive) T cells. Overall, our results, for the first time, show that S100A9 enhances SCLC progression and metastasis by altering the tumor microenvironment, and its inhibition using tasquinimod alone or in combination with chemotherapy could be developed as a promising therapeutic strategy for SCLC.

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options, highlighting the urgent need to define tumor-intrinsic drivers of progression. Here, we uncover a previously unrecognized Psoriasin (S100A7)-driven signaling axis that promotes TNBC growth and identifies cytosolic phospholipase A2 (cPLA2) as a therapeutically actionable vulnerability. Mechanistically, S100A7 engages the RAGE receptor to activate NF-κB, inducing cPLA2, which subsequently upregulates NHERF2 and suppresses GSK3β, sustaining oncogenic signaling that drives proliferation, survival, and metastasis. Disruption of this S100A7→cPLA2→NHERF2 cascade restores GSK3β activity and markedly attenuates tumorigenicity. Genetic ablation of S100A7 in knockout mice or knockdown of NHERF2 suppresses tumor burden, whereas pharmacologic inhibition of GSK3β restores tumor progression, revealing the hierarchical organization and functional importance of this pathway. Using complementary preclinical models, including mammary gland-specific S100A7-overexpressing mice, patient-derived organoids (PDOs), and xenografts (PDXs), we show that targeting this axis, genetically or pharmacologically, effectively suppresses tumor growth and spontaneous metastasis. Notably, combining a cPLA2 inhibitor with our developed first-in-class S100A7-neutralizing antibody produces synergistic anti-tumor effects. Clinically, co-elevation of S100A7 with cPLA2 or NHERF2 associates with poor recurrence-free and distant metastasis-free survival, highlighting the translational relevance of this tumor-intrinsic signaling axis. Collectively, these findings provide both conceptual and translational advances by defining a novel signaling cascade underlying TNBC aggressiveness, revealing an actionable tumor-intrinsic vulnerability, and establishing a rationale for combinatorial interventions that may extend to other cancers with similar intrinsic dependencies.

Small cell lung cancer (SCLC) is the deadliest subtype of lung cancer with a 5-year survival rate of <5% in extensive-state disease and is designated by US Congress as a “recalcitrant cancer”. Recently approved by FDA, immune checkpoint blockade (ICB) immunotherapy showed marginally improved survival and only in a few patients, suggesting an inert immune tumor microenvironment (TME) and the existence of SCLC subtypes. Therefore, there is a significant need to develop more effective therapies for SCLC. In addition to the nearly universal biallelic inactivation of Rb and Tp53 genes in human SCLC tumors, comprehensive genome-wide screening studies have identified major co-occurring mutations in PTEN, CREBBP, EP300, SLIT2, MLL, COBL, and EPHA7 genes. Among them, SLIT2 showed the highest level of genomic abnormalities defined by a pronounced clustering of mutations and frequent genomic loss. However, the role of Slit2 in SCLC has not been defined yet. By using genetically engineered human SCLC cells overexpressing Slit2 or recombinant Slit2 (rSlit2) protein, we show that Slit2 inhibits SCLC cells proliferation, migration, and invasion properties and tumor sphere formation ability of drug-resistant SCLC cells in vitro. The mechanistic studies have identified inhibition of AKT and β-catenin mediated signaling pathways by Slit2 overexpression. Next, we implanted human SCLC cell lines into the immunocompromised NSG mice subcutaneously followed by treatment with rSlit2 or sterile saline. Analysis of tumor volume over the 4 weeks showed that rSlit2 treatment significantly reduced the growth of SCLC tumors. Further analysis of tumors showed that rSlit2 treated tumors harbor less M2-like CD206+ macrophages. Overall, these results suggest that Slit2 possesses tumor suppressive properties and could be developed as a novel therapeutic agent against SCLC. Citation Format: Dinesh K. Ahirwar, Manish Charan, Swati Misri, Konstantin Shilo, Ramesh Ganju. Slit2 inhibits small cell lung cancer by targeting tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2557.

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine disease marked by rapid growth, early metastatic spread, and poor outcomes. The addition of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis to first-line chemotherapy has recently reshaped the treatment landscape for extensive-stage SCLC (ES-SCLC); however, the resulting survival gains remain modest compared with non-small lung cancer (NSCLC). This review explores the molecular features of the SCLC immune landscape that contribute to its predominantly “cold” tumor phenotype, including low MHC class I expression, T-cell exhaustion, and a profoundly immunosuppressive tumor microenvironment (TME). We summarize key clinical findings from landmark trials and examine mechanisms of both primary and acquired resistance against ICIs in SCLC. In addition, we have reviewed the growing role of precision medicine in SCLC, including molecular subtyping (SCLC-A, -N, -P, and -I) and the development of next-generation immunotherapies such as bispecific T-cell engagers (BiTEs), B7-H3, targeted therapy, and antibody–drug conjugates. By combining existing clinical evidence with new molecular insights, this review article presents strategies to overcome the existing therapeutic plateau and enhance personalized immunotherapy approaches in SCLC.