A key reason for the persistently grim statistics associated with metastatic ovarian cancer is resistance to conventional agents, including platinum-based chemotherapies. A major source of treatment failure is the high degree of genetic and molecular heterogeneity, which results from significant underlying genomic instability, as well as stromal and physical cues in the microenvironment. Ovarian cancer commonly disseminates via transcoelomic routes to distant sites, which is associated with the frequent production of malignant ascites, as well as the poorest prognosis. In addition to providing a cell and protein-rich environment for cancer growth and progression, ascitic fluid also confers physical stress on tumors. An understudied area in ovarian cancer research is the impact of fluid shear stress on treatment failure. Here, we investigate the effect of fluid shear stress on response to platinum-based chemotherapy and the modulation of molecular pathways associated with aggressive disease in a perfusion model for adherent 3D ovarian cancer nodules. Resistance to carboplatin is observed under flow with a concomitant increase in the expression and activation of the epidermal growth factor receptor (EGFR) as well as downstream signaling members mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK). The uptake of platinum by the 3D ovarian cancer nodules was significantly higher in flow cultures compared to static cultures. A downregulation of phospho-focal adhesion kinase (p-FAK), vinculin, and phospho-paxillin was observed following carboplatin treatment in both flow and static cultures. Interestingly, low-dose anti-EGFR photoimmunotherapy (PIT), a targeted photochemical modality, was found to be equally effective in ovarian tumors grown under flow and static conditions. These findings highlight the need to further develop PIT-based combinations that target the EGFR, and sensitize ovarian cancers to chemotherapy in the context of flow-induced shear stress.

The increasing incidence of head and neck cancers in South Asia has been described as a global health crisis.¹ Particularly in India, the high incidence of oral cancers is ascribed to the popularity of chewing “gutka” (a compound mixture of tobacco, acacia, and betel nut extracts). The problem of high oral cancer incidence is exacerbated, particularly in rural areas, by limited accessibility of early stage medical screening and imaging. Furthermore, the economic burden of late stage treatments such as complex surgical procedures and/or radiation therapy pose a further barrier in oral cancer management.² Photodynamic therapy (PDT) has emerged as an alternative and noninvasive early stage anticancer treatment modality.³ PDT is a treatment in which a precursor or photosensitizer drug localized to the lesion sites is activated by light to generate singlet oxygen (${}^1{\mathrm{O}}_2$)-mediated photocytotoxicity against cancer cells. Here, we used 5-aminolevulinic acid (ALA as Levulan^®, DUSA, SUN Pharmaceuticals, Inc.), a precursor for the photoactive derivative protoporphyrin IX (PpIX).⁴ PpIX not only acts as a fluorescent probe but also imparts antitumor toxicity when activated by light. This dual functionality has been used successfully for image-guided treatment of various cancers, including those of the oral cavity.^5,6 In clinical settings, PpIX fluorescence and photobleaching make it effective as a diagnostic as well as a treatment monitoring tool.^7,8 Recently, a smartphone with fluorescence imaging capability has been used as a low-cost device for premalignant oral screening.⁸ The wide availability and popularity of smartphones, particularly in the developing countries, make this device promising as a low-cost, portable, and capable theragnostic cancer technology for global health.^{9 – 11} Building on previous preliminary findings,¹² we report here an evaluation of this simple and low-cost fluorescence imaging approach for guidance and monitoring of PDT treatment in the clinic.

In this study, we carry out a pilot clinical evaluation of optical technologies for intraoral imaging and photodynamic therapy (PDT). The optical system for image-guided treatment of oral cancers described here is specifically engineered to address challenges faced in resource-limited clinics and is directly motivated by the public health crisis of oral squamous cell carcinoma (OSCC) in South Asia, where widespread chewing of tobacco-based products (e.g., “gutka”) drives truly alarming rates of oral cancer.¹ In particular, in India, where there is a lack of widespread access to medical infrastructure for cancer management, the rate of new age-adjusted oral cancer cases is 36% (135,929), and the mortality rate is 42.4% (75,290 deaths). The World Health Organization projected that new oral cancer cases would increase to 209,000 (65%) and death would be 116,000 (65%) in India by 2040.² Due to a lack of routine oral examination and timely biopsy, late-stage diagnosis is the norm in India, with 70% of cases presenting at stage III-IV.³ As a result, even those patients in rural areas who undergo conventional treatment with surgery and/or chemotherapy show a 5-year survival rate of $<50\%$.⁴ Clearly, there is an urgent need for new technologies that can help enable timely diagnosis and treatment of oral malignancy in challenging, resource-limited rural clinics. Such technologies must be specifically engineered to be produced at low cost, portable, easy to use, and functional in settings with limited infrastructure. In the present report, we demonstrate the integration of previously reported low-cost technology for PDT with an intraoral optical imaging probe previously validated for oral cancer detection and adapted here for image guidance of PDT.^{5 – 7}