Joseph Carmicheal

Radiation therapy (RT) is a mainstay of treatment for a myriad of cancers, often utilized for tumors that are unable to be resected, as well as an adjunct to surgery and chemotherapy. Unfortunately, many cancers are resistant to RT‐induced damage and subsequent cell death. This has spurred the pursuit of novel radiation sensitizers that could potentiate the effects of this widely used and important treatment modality. Since its discovery as a regulated cell death mechanism in 2012, ferroptosis has been studied for its connection to cancer and other known oxidative pathways. With this, the interplay between RT and ferroptosis in cancer has recently begun to be explored. Radiation increases reactive oxygen species (ROS), facilitates lipid peroxidation, and releases free ferrous iron, all of which directly impact the ferroptotic pathway. In conjunction, RT has been shown to induce the expression of ferroptosis‐related molecules (e.g., SLC7A11, GPX4) through the P62‐KEAP1‐NRF2 pathway, thereby preventing cell death via ferroptosis. The use of ferroptosis inducers (FINs) to block these antioxidant mechanisms is a promising area of study as pharmacological radiosensitizers to improve the efficacy of RT and patient outcomes. In this comprehensive narrative review, the molecular connections between ferroptosis, cancer, and radiation will be discussed, the preponderance of existing literature investigating the potential of FINs as radiosensitizers will be presented, and possible areas of future study will be offered.

Radiation therapy (RT) has long been an important part of the history of curative treatment for Hodgkin Lymphoma since the pioneering work of Vera Peters, MD and Henry Kaplan, MD. The contemporary role of radiation therapy in the management of patients with early-stage favorable and unfavorable disease, advanced disease, and relapsed/refractory disease will be explored. Seminal clinical trials that highlight the critical role of RT in local control and progression-free survival will be reviewed. The interest in combined modality therapy (CMT) (combination of chemotherapy and RT) will be explored as well as the use of CMT with emphasis on cost effectiveness, age and sex, and risk profile including secondary malignancy and cardiac toxicity compared with chemotherapy alone. Contemporary radiation treatment volumes, techniques, and doses will be discussed as modern strategies to mitigate late toxicities while maintaining efficacy.

Primary central nervous system choriocarcinoma is a non-germinomatous germ cell tumor with a highly malignant character, comprising up to 5% of all central nervous system germ cell tumors. Locations affected can include suprasellar or pineal locations most commonly, with others including the basal ganglia and lateral ventricles. Guidelines do not specify an optimal radiation regimen but recommend proceeding with maximally safe resection if feasible and then chemotherapy before radiotherapy. Radiation is often comprised of craniospinal irradiation with subsequent tumor bed boost. We present a case of an adult male with a primary central nervous system choriocarcinoma who underwent reversed sequence radiation therapy with photon tumor bed boost before proton craniospinal irradiation due to recurrent intracranial hemorrhages with long-term control of cancer and no subsequent hemorrhages. This case highlights the excellent outcome and feasibility of reversed sequence radiotherapy on choriocarcinoma in hemorrhage and tumor control.

Background: Radiotherapy plays a fundamental role in the treatment of patients with all stages of non‐small‐cell lung cancer (NSCLC). The emergence of immune checkpoint inhibitors (ICIs) has transformed the standard of care in these patients. The use of ICIs is increasingly utilized in the definitive setting as an adjunct to chemoradiotherapy or surgery and remains a vital component in the treatment of metastatic disease. Despite improvements in patient survival, the use of immunotherapy as monotherapy has shown limited overall response rates with susceptibility to resistance. Radiotherapy has been identified as a viable option to enhance the response rate to ICI and improve outcomes in NSCLC. Methods: We queried the English PubMed database utilizing variably combined search items including “radiation,” “chemoradiation,” “immune checkpoint,” “immunotherapy,” “stereotactic body radiotherapy,” and “non‐small‐cell lung”. We additionally searched various acceptable alternative terms for similar keywords such as “radiotherapy” in place of “radiation.” These results were subsequently curated for relevance and impact on current treatment paradigms. Results: In this review, we discuss preclinical and clinical studies relating to combinatorial use of immunotherapy and radiation in NSCLC. These studies are presented in the context of early‐stage, operable stage III, unresectable stage III, and metastatic disease. The majority of the data illustrate promising results regarding the additive or synergistic effects of radiation and immunotherapy with a suggestion that the timing of these treatment modalities is crucial to optimizing outcomes. Conclusion: While there is now evidence regarding the favorable interplay between radiation and immunotherapy in NSCLC, there remain multiple unanswered questions which are expected to be addressed in ongoing clinical trials.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to limited therapeutic options and expensive/burdensome drug discovery processes. Utilizing genomic-data-driven Connectivity Mapping (CMAP) to identify a drug closer to real-world PC targeting may improve pancreatic cancer (PC) patient outcomes. Initially, we mapped CMAP data to gene expression from 106 PC patients, identifying nine negatively connected drugs. These drugs were further narrowed down using a similar analysis for PC cell lines, human tumoroids, and patient-derived xenografts datasets, where ISOX emerged as the most potent agent to target PC. We used human and mouse syngeneic PC cells, human and mouse tumoroids, and in vivo mice to assess the ability of ISOX alone and in combination with 5FU to inhibit tumor growth. Global transcriptomic and pathway analysis of the ISOX-LINCS signature identified HDAC 6/cMyc as the target axis for ISOX. Specifically, we discovered that genetic and pharmacological targeting of HDAC 6 affected non-histone protein cMyc acetylation, leading to cMyc instability, thereby disrupting PC growth and metastasis by affecting cancer stemness. Finally, Kras^G12D harboring tumoroids and mice responded effectively against ISOX and 5FU treatment by enhancing survival and controlling metastasis incidence. Overall, our data validate ISOX as a new drug to treat advanced PC patients without toxicity to normal cells. Our study supports the clinical utility of ISOX along with 5FU in future PC clinical trials.

SERS immunoassay biosensors hold immense potential for clinical diagnostics due to their high sensitivity and growing interest in multi-marker panels. However, their development has been hindered by difficulties in designing compatible extrinsic Raman labels. Prior studies have largely focused on spectroscopic characteristics in selecting Raman reporter molecules (RRMs) for multiplexing since the presence of well-differentiated spectra is essential for simultaneous detection. However, these candidates often induce aggregation of the gold nanoparticles used as SERS nanotags despite their similarity to other effective RRMs. Thus, an improved understanding of factors affecting the aggregation of RRM-coated gold nanoparticles is needed. Substituent electronic effects on particle stability were investigated using various para-substituted thiophenols. The inductive and resonant effects of functional group modifications were strongly correlated with nanoparticle surface charge and hence their stability. Treatment with thiophenols diminished the negative surface charge of citrate-stabilized gold nanoparticles, but electron-withdrawing substituents limited the magnitude of this diminishment. It is proposed that this phenomenon arises by affecting the interplay of competing sulfur binding modes. This has wide-reaching implications for the design of biosensors using thiol-modified gold surfaces. A proof-of-concept multiplexed SERS biosensor was designed according to these findings using the two thiophenol compounds with the most electron-withdrawing substitutions: NO₂ and CN.

Radiotherapy promotes tumor cell death and senescence through the induction of oxidative damage. Recent work has highlighted the importance of lipid peroxidation for radiotherapy efficacy. Excessive lipid peroxidation can promote ferroptosis, a regulated form of cell death. In this review, we address the evidence supporting a role of ferroptosis in response to radiotherapy and discuss the molecular regulators that underlie this interaction. Finally, we postulate on the clinical implications for the intersection of ferroptosis and radiotherapy.

Lung cancer (LC) is the leading cause of cancer‐related mortality. However, the molecular mechanisms associated with the development of metastasis are poorly understood. Understanding the biology of LC metastasis is critical to unveil the molecular mechanisms for designing targeted therapies. We developed two genetically engineered LC mouse models Kras^G12D/+; Trp53^R172H/+; Ad‐Cre (KPA) and Kras^G12D/+; Ad‐Cre (KA). Survival analysis showed significantly (P = 0.0049) shorter survival in KPA tumor‐bearing mice as compared to KA, suggesting the aggressiveness of the model. Our transcriptomic data showed high expression of N‐acetylgalactosaminide alpha‐2, 6‐sialyltransferase 1 (St6galnac‐I) in KPA compared to KA tumors. ST6GalNAc‐I is an O‐glycosyltransferase, which catalyzes the addition of sialic acid to the initiating GalNAc residues forming sialyl Tn (STn) on glycoproteins, such as mucins. Ectopic expression of species‐specific p53 mutants in the syngeneic mouse and human LC cells led to increased cell migration and high expression of ST6GalNAc‐I, STn, and MUC5AC. Immunoprecipitation of MUC5AC in the ectopically expressing p53^R175H cells exhibited higher affinity toward STn. In addition, ST6GalNAc‐I knockout (KO) cells also showed decreased migration, possibly due to reduced glycosylation of MUC5AC as observed by low STn on the glycoprotein. Interestingly, ST6GalNAc‐I KO cells injected mice developed less liver metastasis (P = 0.01) compared to controls, while colocalization of MUC5AC and STn was observed in the liver metastatic tissues of control mice. Collectively, our findings support the hypothesis that mutant p53^R175H mediates ST6GalNAc‐I expression, leading to the sialyation of MUC5AC, and thus contribute to LC liver metastasis.

Metastasis of breast cancer (BC) is the leading cause of mortality in American women. In particular, brain metastasis is a significant clinical problem present in 30-40% of triple receptor negative (TN) and epidermal growth factor receptor 2 (HER2) positive BC patients. These patients also have the worst prognosis of all breast cancers in women. Due to advances in clinical management at both the diagnostic and therapeutic levels, the lifespan or overall survival of these patients has increased, but the manifestation of brain metastasis at later stages of the disease remains an unfortunate burden for these patients. In addition, the blood-brain barrier (BBB) poses an additional hurdle for treatment of BC brain metastases, because the majority of chemotherapeutic drugs fail to cross the BBB. Furthermore, there is no single targeted therapy available for TNBC patients with brain metastasis, and thus there is an urgent requirement to discover novel biomarkers and therapeutics to address BC brain metastasis. In this regard, using a bioinformatics approach, we observed that several mucins, including MUC5AC, are significantly up-regulated in brain metastases of BC compared to primary tumors. However, we found the secretory mucin MUC5AC protein to be substantially high in brain-seeking BC (BSBC) cell lines and metastatic brain tissues. We also observed that knockdown of MUC5AC reduced proliferation and metastatic potential in these cell lines. Furthermore, we observed that MUC5AC colocalizes with activated MET receptor. MUC5AC knockdown in BSBC cell lines reduced MET activation and its downstream targets FAK and paxillin. Interestingly, MET and FAK inhibition using pharmacological inhibitors led to substantial decrease in MUC5AC expression. Overall, these studies suggest that MUC5AC-MET axis may regulate breast cancer brain metastasis. Understanding the MUC5AC-MET axis could be a novel approach for the development of better prognosis and prevention of life-threatening and treatment-resistant breast cancer brain metastasis. Citation Format: Mohd W. Nasser, Shailendra K. Gautam, Ranjana Kanchan, Pranita Atri, Jawed Siddiqui, Rakesh Bhatia, Joseph Carmicheal, Dario Ghersi, Sukhwinder Kaur, Siddharth Mahapatra, Maneesh Jain, Surinder K. Batra. Elucidating the role of MUC5AC-MET axis in breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 50.