Gaurav Sharma

Purpose of review: Pain is a major source of morbidity in head and neck cancer (HNC), yet its neural mechanisms remain incompletely defined. This review examines how malignant cells, the tumor microenvironment, and cancer treatment remodel peripheral sensory and autonomic circuits, and how neural activity reciprocally influences tumor biology, with particular attention to findings published since 2023. Recent findings: Recent studies show that HNC selectively reorganizes tumor-associated nerves rather than merely injuring a pre-existing neural scaffold. Sensory-neuron transcriptional responses differ by sex, perineural invasion redistributes mechanosensory and nociceptive activity, and cancer-induced injury establishes sympathetic-sensory crosstalk. Tumor-derived extracellular vesicles can program persistent nociceptor hypersensitivity, while adenosine-A2A, protease-PAR2, NGF-neuropilin-1, and EGFR pathways connect tumor metabolism and signaling to neuronal excitability and analgesic tolerance. Conversely, sensory and sympathetic signals promote tumor growth through direct effects on malignant cells, metabolic reprogramming, and local or systemic immune suppression. Surgery and radiotherapy add distinct patterns of denervation, sensitization, and reparative remodeling. Summary: HNC pain arises from reciprocal remodeling across tumor, immune, stromal, glial, and neural compartments. Defining how these circuits generate clinical pain phenotypes may support mechanism-based analgesia while avoiding unintended effects on antitumor immunity, tumor progression, or treatment response.

Ovarian cancer remains the most lethal gynecologic malignancy, driven in part by intrinsic and acquired therapeutic resistance to DNA-damaging chemotherapies. We previously demonstrated that ERX-208 targets the protein encoded by lysosomal acid lipase to induce catastrophic endoplasmic reticulum (ER) stress in ovarian cancer models. As ERX-class compounds advance to clinical development, rational combination strategies are needed to maximize therapeutic efficacy. To address this question, we conducted an unbiased in vitro screen of the combination of ERX-208 with 147 FDA-approved agents. We identified that DNA-damaging chemotherapies, including anthracyclines, oxaliplatin, and paclitaxel, were most synergistic in combination with ERX-208. Reanalysis of our transcriptomic data in ovarian cancer cells revealed coordinated suppression of DNA damage repair, DNA replication, and checkpoint pathways following ERX-208 treatment. Together, these data support a narrative that ERX-208 may selectively suppress DNA repair pathways and potentiate cytotoxicity by DNA-damaging agents. To test this hypothesis, we used platinum and paclitaxel, two standard-of-care agents in ovarian cancer. We found that ERX-208 synergized with platinum and paclitaxel across multiple ovarian cancer models, enhancing apoptosis and suppressing proliferation, clonogenicity, and invasion. Mechanistically, combination treatment increased DNA damage and amplified ER stress and apoptotic signaling. Importantly, ERX-208–based combinations showed enhanced antitumor activity in patient-derived explant, and xenograft models. These findings support a model in which ERX-208 impairs DNA damage response pathways and sensitizes ovarian cancer cells to DNA-damaging chemotherapy. Collectively, these findings provide a strong rationale for the combination strategy in clinical translation. Significance: This study demonstrates the clinical utility of ERX-208 in enhancing chemotherapy efficacy in ovarian cancer. By inducing sustained ER stress and a functional DNA repair–deficient state, ERX-208 sensitizes treatment-naïve and treatment-resistant tumors to platinum and taxanes. Findings support the rapid clinical development of ERX-class combinations, offering a rationale for pairing with standard regimens. This strategy may enable dose reduction, overcome resistance, expand options, and support biomarker-guided patient selection.

Approximately 2–4% of all breast cancer cases are inflammatory breast cancer (IBC), an extremely rare and severe subtype of the disease. Current therapies, including chemotherapy, surgery, and radiotherapy, remain insufficient, underscoring the need for novel therapeutic approaches. IBC exhibits elevated basal endoplasmic reticulum (ER) stress, suggesting a potential vulnerability. We recently developed ERX-41, a small molecule that exacerbates ER stress in cancer cells by inhibiting the endoplasmic reticulum-localized function of Lysosomal acid lipase A (LIPA). Here, we evaluated the therapeutic potential of ERX-41 in IBC models. ERX-41 markedly reduced the viability of IBC cells and significantly impaired clonogenic survival while promoting apoptosis. The specificity of ERX-41 was confirmed using LIPA-knockdown and LIPA-knockout cells. RT-PCR-based assays revealed rapid induction of XBP1 splicing within 6 h of treatment, and Western blot analyses demonstrated activation of ER stress markers including CHOP, PERK, and ATF4. In KPL4 xenografts, ERX-41 treatment significantly decreased tumor volume, accompanied by reduced proliferation and increased ER stress marker expression by IHC. Collectively, these findings identify LIPA as a therapeutically actionable vulnerability in IBC and establish ERX-41 as a potential drug for IBC.

Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.