Neoadjuvant photodynamic therapy augments immediate and prolonged oxaliplatin efficacy in metastatic pancreatic cancer organoids

Abstract

Effective treatment of advanced metastatic disease remains the primary challenge in the management of inoperable pancreatic cancer. Current therapies such as oxaliplatin (OxPt)-based chemotherapy regimens (FOLFIRINOX) provide modest short-term survival improvements, yet with significant toxicity. Photodynamic therapy (PDT), a light-activated cancer therapy, demonstrated clinical promise for pancreatic cancer treatment and enhances conventional chemotherapies with non-overlapping toxicities. This study investigates the capacity of neoadjuvant PDT using a clinically-approved photosensitizer, benzoporphyrin derivative (BPD, verteporfin), to enhance OxPt efficacy in metastatic pancreatic cancer. Treatment effects were evaluated in organotypic three-dimensional (3D) cultures, clinically representative models that bridge the gap between conventional cell cultures and in vivo models. The temporally-spaced, multiparametric analyses demonstrated a superior efficacy for combined PDT+OxPt compared to each monotherapy alone, which was recapitulated on different organotypic pancreatic cancer cultures. The therapeutic benefit of neoadjuvant PDT to OxPt chemotherapy materialized in a time-dependent manner, reducing residual viable tissue and tumor viability in a manner not achievable with OxPt or PDT alone. These findings emphasize the need for intelligent combination therapies and relevant models to evaluate the temporal kinetics of interactions between mechanistically-distinct treatments and highlight the promise of PDT as a neoadjuvant treatment for disseminated pancreatic cancer.

Cabozantinib Inhibits Photodynamic Therapy-Induced Auto- and Paracrine MET Signaling in Heterotypic Pancreatic Microtumors

“…We next evaluated whether the presence of MRC5 in AsPC-1 spheroids influenced the efficacy of PDT. In radiant exposure dose-escalation experiments (timeline in Figure 3 A), we combined in situ live/dead staining with a recently developed automated image analysis tool for multiparametric assessment of treatment effects [ 18 , 26 , 27 ]. In this study, we evaluated treatment responses by quantifying viability, necrosis, spheroid area, fractional live area, and fractional dead area.…”

“…PDT involves the selective activation of a photosensitizing agent in tumor tissues by light irradiation, resulting in the local generation of reactive molecular species that cause severe oxidative stress, vascular damage followed by tumor anoxia, and the onset of anti-tumor immune responses [12][13][14][15]. Through these distinctive mechanisms and with non-overlapping toxicities, (neo)adjuvant PDT was shown to augment the efficacy of gemcitabine, oxaliplatin, irinotecan, metformin, and EGFR-inhibitors in preclinical cancer models [16][17][18][19][20][21][22][23]. Our group recently developed a photoactivatable drug delivery system containing the photosensitizer benzoporphyrin derivative (BPD) and cabozantinib.…”

Thomas J. Dougherty: An Appreciation

“…There continues to be support for three major PDT research groups (University of Pennsylvania, Massachusetts General Hospital/Harvard and Roswell Park Cancer Center). There are implications for use of PDT in otherwise poorly‐responsive tumors, for example, pancreatic cancer and mesothelioma . At this point, an appreciation for what PDT can do appears to be limited to a few centers in the US.…”

Organoid technology and applications in cancer research

“…Photodynamic therapy, known as a light-activated cancer therapy, supplements conventional chemotherapies and brings clinical promise for pancreatic cancer treatment [ 118 ]. As observed in organoids of metastatic pancreatic carcinoma, intelligent combination of oxaliplatin and neoadjuvant photodynamic therapy exhibited remarkably enhanced anti-tumor efficacy in comparison with any therapy alone, without augment of toxicity [ 118 ].…”