Maria Poimenidou

Accumulating evidence indicates that evasion of apoptosis and metabolic reprogramming are necessary for pancreatic cancer growth, early invasion, and chemotherapeutic resistance. Building on our prior work, we investigated the anti-tumor potential of a rationally designed mitochondria-targeted variant of the anti-diabetic drug metformin, Mito-Met ₁₀ , in cell culture models and orthotopic xenografts. Using MALDI-mass spectrometry imaging, therapeutic concentrations of fluorinated Mito-Met ₁₀ were shown to preferentially localize within pancreatic tumors relative to adjacent tissue and liver. Treatment suppressed tumor growth, reduced tumor weights, and increased apoptosis in vivo. Murine and human pancreatic cancer cells demonstrated potent anti-proliferative activity, with low micromolar IC ₅₀ values, and a concomitant induction of apoptotic programmed cell death in vitro. Seahorse metabolic flux analysis revealed reduced basal and ATP-linked mitochondrial respiration following Mito-Met ₁₀ treatment without a compensatory increase in glycolysis. Unbiased bulk RNA sequencing revealed significant enrichment of endoplasmic reticulum stress and unfolded protein response pathways, validated by qPCR across pancreatic cancer models, with broad upregulation of UPR-associated genes, establishing that Mito-Met ₁₀ activation of this stress response is conserved. Mito-Met ₁₀ caused extensive cytoplasmic vacuolization, mitochondrial swelling, and loss of mitochondrial membrane potential, indicative of severe organelle damage. Mito-Met ₁₀ activated PERK-eIF2α-ATF4-CHOP signaling, including upregulation of ATF4 and downstream pro-apoptotic transcriptional programs. Pharmacologic inhibition of ISR abrogated apoptotic signaling, demonstrating that PERK-eIF2α-ATF4-CHOP-mediated ISR activation functionally contributes to the anti-tumor effects of Mito-Met ₁₀ . Consistent with these findings, orthotopic tumors from Mito-Met ₁₀ -treated mice exhibited increased nuclear ATF4 staining compared with vehicle controls. Collectively, this study links mitochondrial stress to ER stress-associated apoptosis and identifies mitochondrial stress as a tractable vulnerability that can be manipulated to positively engage anti-tumor responses in pancreatic cancer.

Surgery for local control is a cornerstone of anticancer therapy with demonstrated survival benefit. However, surgery-induced modulation of antitumor immunity may also contribute to cancer progression and relapse. Despite evidence for a pro-tumor surgery effect in adult cancers, there remain significant knowledge gaps as to the influence surgery has on recurrence or metastatic outgrowth in pediatric cancers. High-risk neuroblastoma (HR-NB) is the most common extracranial solid tumor of childhood. While almost all children with HR-NB undergo surgery, nearly 50% suffer metastatic relapse and succumb to their disease. To ascertain if surgery may contribute to recurrence in HR-NB, we developed a mouse model to comprehensively interrogate the systemic effect of surgery on distant tumor growth and immune modulation. This model demonstrated that MYCN-amplified HR-NB tumor growth was accelerated by surgery compared to tumor-bearing mice without surgical stress. Accelerated tumor growth was absent in HR-NB cells engrafted to immune deficient mice, suggesting that an intact immune system may be needed for surgery to exert its pro-growth effect on distant tumor cells. Consistent with that genetic ablation model, flow cytometry measured a decrease in splenic macrophages (Mϕ) and dendritic cells (DC) and an increase in myeloid-derived suppressor cells (MDSC) after surgery. Perioperative treatment with polyinosinic-polycytidylic acid [poly(I:C)] ameliorated surgery-induced tumor growth. These findings provide direct insight into the systemic surgical effect on pediatric solid tumor growth and identify innate immune adjuvants as a potential perioperative treatment to mitigate this effect.

Neuroblastoma (NBL) cells highly express disialoganglioside GD2, which is restricted and weakly expressed in selected healthy cells, making it a desirable target of immunotherapy. Over the past two decades, application of dinutuximab, an anti-GD2 monoclonal antibody (mAb), has been one of the few new therapies to substantially improve outcomes to current levels. Given the persistent challenge of relapse and therapeutic resistance, there is an urgent need for new effective and tolerable treatment options for high-risk NBL. Recent breakthroughs in immune checkpoint inhibitor (ICI) therapeutics have not translated into high-risk NBL, like many other major pediatric solid tumors. Given the suppressed tumor microenvironment (TME), single ICIs like anti-CTLA4 and anti-PD1 have not demonstrated significant antitumor response rates. Meanwhile, emerging studies are reporting novel advancements in GD2-based therapies, targeted therapies, nanomedicines, and other immunotherapies such as adoptive transfer of natural killer (NK) cells and chimeric antigen receptors (CARs), and these hold interesting promise for the future of high-risk NBL patient care. Herein, we summarize the current state of the art in NBL therapeutic options and highlight the unique challenges posed by NBL that have limited the successful adoption of immune-modifying therapies. Through this review, we aim to direct the field’s attention to opportunities that may benefit from a combination immunotherapy strategy.