Auranofin repurposing for lung and pancreatic cancer: low CA12 expression as a marker of sensitivity in patient-derived organoids, with potentiated efficacy by AKT inhibition.

BACKGROUND: This study explores the repurposing of Auranofin (AF), an anti-rheumatic drug, for treating non-small cell lung cancer (NSCLC) adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). Drug repurposing in oncology offers a cost-effective and time-efficient approach to developing new cancer therapies. Our research focuses on evaluating AF's selective cytotoxicity against cancer cells, identifying RNAseq-based biomarkers to predict AF response, and finding the most effective co-therapeutic agents for combination with AF. METHODS: Our investigation employed a comprehensive drug screening of AF in combination with eleven anticancer agents in cancerous PDAC and NSCLC patient-derived organoids (n = 7), and non-cancerous pulmonary organoids (n = 2). Additionally, we conducted RNA sequencing to identify potential biomarkers for AF sensitivity and experimented with various drug combinations to optimize AF's therapeutic efficacy. RESULTS: The results revealed that AF demonstrates a preferential cytotoxic effect on NSCLC and PDAC cancer cells at clinically relevant concentrations below 1 µM, sparing normal epithelial cells. We identified Carbonic Anhydrase 12 (CA12) as a significant RNAseq-based biomarker, closely associated with the NF-κB survival signaling pathway, which is crucial in cancer cell response to oxidative stress. Our findings suggest that cancer cells with low CA12 expression are more susceptible to AF treatment. Furthermore, the combination of AF with the AKT inhibitor MK2206 was found to be particularly effective, exhibiting potent and selective cytotoxic synergy, especially in tumor organoid models classified as intermediate responders to AF, without adverse effects on healthy organoids. CONCLUSION: Our research offers valuable insights into the use of AF for treating NSCLC and PDAC. It highlights AF's cancer cell selectivity, establishes CA12 as a predictive biomarker for AF sensitivity, and underscores the enhanced efficacy of AF when combined with MK2206 and other therapeutics. These findings pave the way for further exploration of AF in cancer treatment, particularly in identifying patient populations most likely to benefit from its use and in optimizing combination therapies for improved patient outcomes.

A systematic review of patient-derived tumor organoids generation from malignant effusions.

This review assesses the possibility of utilizing malignant effusions (MEs) for generating patient-derived tumor organoids (PDTOs). Obtained through minimally invasive procedures MEs broaden the spectrum of organoid sources beyond resection specimens and tissue biopsies. A systematic search yielded 11 articles, detailing the successful generation of 190 ME-PDTOs (122 pleural effusions, 54 malignant ascites). Success rates ranged from 33% to 100%, with an average of 84% and median of 92%. A broad and easily applicable array of techniques can be employed, encompassing diverse collection methods, variable centrifugation speeds, and the inclusion of approaches like RBC lysis buffer or centrifuged ME supernatants supplementation, enhancing the versatility and accessibility of the methodology. ME-PDTOs were found to recapitulate primary tumor characteristics and were primarily used for drug screening applications. Thus, MEs are a reliable source for developing PDTOs, emphasizing the need for further research to maximize their potential, validate usage, and refine culturing processes.

Immediate hypersensitivity reactions to antineoplastic agents - A practical guide for the oncologist.

Immediate hypersensitivity reactions (IHRs) to antineoplastic agents occur frequently, and every oncologist will encounter these reactions in their clinical practice at some point. The clinical signature of IHRs can range from mild to life-threatening, and their occurrence can substantially impede the treatment course of patients with cancer. Yet, clear guidelines regarding the diagnosis and management are scarce, especially from an oncologic point of view. Therefore, herein, we review the definition, pathophysiology, epidemiology, diagnosis and management of IHRs to chemotherapeutic agents and monoclonal antibodies. First, we focus on defining the specific entities that comprise IHRs and discuss their underlying mechanisms. Then, we summarize the epidemiology for the antineoplastic agents that represent the most common causes of IHRs, i.e., platinum compounds, taxanes and monoclonal antibodies (mAbs). Next, we describe the possible clinical pictures and the comprehensive diagnostic work-up that should be executed to identify the culprit and safe alternatives for the future. Finally, we finish with reviewing the treatment options in both the acute phase and after recovery, with the aim to improve the oncologic care of patients with cancer.

mRNA-LNP vaccines tuned for systemic immunization induce strong antitumor immunity by engaging splenic immune cells.

mRNA vaccines have recently proved to be highly effective against SARS-CoV-2. Key to their success is the lipid-based nanoparticle (LNP), which enables efficient mRNA expression and endows the vaccine with adjuvant properties that drive potent antibody responses. Effective cancer vaccines require long-lived, qualitative CD8 T cell responses instead of antibody responses. Systemic vaccination appears to be the most effective route, but necessitates adaptation of LNP composition to deliver mRNA to antigen-presenting cells. Using a design-of-experiments methodology, we tailored mRNA-LNP compositions to achieve high-magnitude tumor-specific CD8 T cell responses within a single round of optimization. Optimized LNP compositions resulted in enhanced mRNA uptake by multiple splenic immune cell populations. Type I interferon and phagocytes were found to be essential for the T cell response. Surprisingly, we also discovered a yet unidentified role of B cells in stimulating the vaccine-elicited CD8 T cell response. Optimized LNPs displayed a similar, spleen-centered biodistribution profile in non-human primates and did not trigger histopathological changes in liver and spleen, warranting their further assessment in clinical studies. Taken together, our study clarifies the relationship between nanoparticle composition and their T cell stimulatory capacity and provides novel insights into the underlying mechanisms of effective mRNA-LNP-based antitumor immunotherapy.

The association between type of endocrine therapy and development of estrogen receptor-1 mutation(s) in patients with hormone-sensitive advanced breast cancer: A systematic review and meta-analysis of randomized and non-randomized trials.

BACKGROUND: Breast cancer has, due to its high incidence, the highest mortality of cancer in women. The most common molecular type of breast cancer is the luminal subtype, which expresses estrogen and progesterone receptors and is typically treated with surgery and adjuvant endocrine therapy (ET). Estrogen receptor alpha (ERα), encoded by the estrogen receptor-1 (ESR1) gene, is expressed in approximately 70% of all breast cancers, and ET represents a major treatment modality in ERα-positive cancers. However, resistance to different ET evolves frequently, leading to disease progression or recurrence in ER+ breast cancer. Acquired mutations in the Ligand Binding Domain (LBD) of the ERα referred as ESR1 mutations; could be selected by ET itself leading to resistance over the course of ET therapy. OBJECTIVE: The goal of this review is to estimate the effect of Aromatase Inhibitors (AIs), Tamoxifen (TAM) and Fulvestrant (FUL) on the development of ESR1 mutations in hormone-sensitive advanced breast cancer. METHODS: A systematic review of qualitative studies published between January 1st, 2007 and March 1st, 2019 was conducted using the PubMed and Thomas Reuters Web of Science databases. Search terms included ESR1 mutations, estrogen receptor, breast cancer, recurrent, metastatic disease, aromatase inhibitors, fulvestrant and tamoxifen. Only full-text studies in English concerning the development of ESR1 mutations and their outcomes on disease progression were included. Selection of studies was performed using predefined data fields, taking study quality indicators into consideration. Inclusion criteria of the study populations were: Ghoncheh et al. (2016) [1] female patients above 18 years; Nielsen et al. (2011) [2] Estrogen-receptor positive (ER+) breast cancer in the advanced setting; Reinert et al. (2017) [3] previous exposure to endocrine therapy including SERDs (preferably Fulvestrant), SERMs (preferably Tamoxifen) or Aromatase Inhibitors. RESULTS: The current review enrolled 16 articles, including 4 multicentre double blinded RCTs and 12 cohorts and comprising a total of 2632 patients. The overall incidence rate of the ESR1 mutation was 24% (95% CI: 18%-31%). We observed that D538G was the most frequent ESR1 mutation. Several studies showed that prior endocrine therapy (AIs, TAM, FUL) could result in an ESR1 mutation and therapy resistance leading to disease progression or recurrence. Different mechanisms had been implied to explain the underlying ET resistance. One of the key findings of this work is the significant difference in ESR1 mutation incidence between patients with and without AI therapy (OR: 9.34, 95% CI: 3.28-26.62, P ≤.001). CONCLUSION: ESR1 mutations are not uncommon phenomenon in patients with hormone-sensitive advanced breast cancer. There is a significant higher incidence rate of ESR1 mutations in patients with previous AI-containing therapeutic regimens, compared to those who received non-AI containing regimes. These ESR1 mutations could lead to the development of complete endocrine resistance to AI, whereas only partial resistance is seen in case of TAM or FUL.

Design of a Mesoscale Continuous-Flow Route toward Lithiated Methoxyallene.

The unique nucleophilic properties of lithiated methoxyallene allow for C-C bond formation with a wide variety of electrophiles, thus introducing an allenic group for further functionalization. This approach has yielded a tremendously broad range of (hetero)cyclic scaffolds, including precursors to active pharmaceutical ingredients. To date, however, its valorization at scale is hampered by the batch synthesis procedure, which suffers from serious safety issues. Hence, the attractive heat- and mass-transfer properties of flow technology were exploited to establish a mesoscale continuous-flow route toward lithiated methoxyallene. An excellent conversion of 94 % was obtained, corresponding to a methoxyallene throughput of 8.2 g h-1 . The process is characterized by short reaction times, mild reaction conditions and a stoichiometric use of reagents.

Enhancing Zeolite Performance by Catalyst Shaping in a Mesoscale Continuous-Flow Diels-Alder Process.

In contrast to most lab-scale batch procedures, a continuous-flow implementation requires a thorough consideration of the solid catalyst design. In a previous study, irregular zeolite pellets were applied in a miniaturized continuous-flow reactor for the Diels-Alder reaction in the construction of norbornene scaffolds. After having faced the challenges of continuous operation, the aim of this study is to exploit catalyst structuring. To this end, microspheres with high uniformity and various sphere diameters were synthesized according to the vibrational droplet coagulation method. The influence of the use of these novel zeolite shapes in a mesoscale continuous-flow Diels-Alder process of cyclopentadiene and methyl acrylate is discussed. An impressive enhancement of catalyst lifetime is demonstrated, as even after a doubled process time of 14 h, the microspheres still exceeded the conversion after 7 h when using zeolite pellets by 30 %. A dual reason is found for this beneficial impact of catalyst shaping. The significant improvement in catalyst longevity can be attributed to the interplay of the chemical composition and the porosity structure of the microspheres.