An international phase II trial and immune profiling of SBRT and atezolizumab in advanced pretreated colorectal cancer.

BACKGROUND: Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients. METHODS: Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling. RESULTS: Sixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20-81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9-11.6] and 1.4 months [95%CI:1.2-2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses. CONCLUSIONS: This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy. TRIAL REGISTRATION: EudraCT N°: 2015-005464-42; Clinicaltrial.gov number: NCT02992912.

KRASG12C inhibition using MRTX1257: a novel radio-sensitizing partner.

BACKGROUND: KRAS activating mutations are considered the most frequent oncogenic drivers and are correlated with radio-resistance in multiple cancers including non-small cell lung cancer (NSCLC) and colorectal cancer. Although KRAS was considered undruggable until recently, several KRAS inhibitors have recently reached clinical development. Among them, MRTX849 (Mirati Therapeutics) showed encouraging clinical outcomes for the treatment of selected patients with KRASG12C mutated NSCLC and colorectal cancers. In this work, we explore the ability of MRTX1257, a KRASG12C inhibitor analogous to MRTX849, to radio-sensitize KRASG12C+/+ mutated cell lines and tumors. METHODS: Both in vitro and in vivo models of radiotherapy (RT) in association with MRTX1257 were used, with different RAS mutational profiles. We assessed in vitro the radio-sensitizing effect of MRTX1257 in CT26 KRASG12C+/+, CT26 WT, LL2 WT and LL2 NRAS KO (LL2 NRAS-/-) cell lines. In vivo, we used syngeneic models of subcutaneous CT26 KRASG12C+/+ tumors in BALB/c mice and T cell deficient athymic nu/nu mice to assess both the radio-sensitizing effect of MRTX1257 and its immunological features. RESULTS: MRTX1257 was able to radio-sensitize CT26 KRASG12C+/+ cells in vitro in a time and dose dependent manner. Moreover, RT in association with MRTX1257 in BALB/c mice bearing CT26 KRASG12C+/+ subcutaneous tumors resulted in an observable cure rate of 20%. However, no durable response was observed with similar treatment in athymic nude mice. The analysis of the immune microenvironment of CT26 KRASG12C+/+ tumors following RT and MRTX1257 showed an increase in the proportion of various cell subtypes including conventional CD4 + T cells, dendritic cells type 2 (cDC2) and inflammatory monocytes. Furthermore, the expression of PD-L1 was dramatically down-regulated within both tumor and myeloid cells, thus illustrating the polarization of the tumor microenvironment towards a pro-inflammatory and anti-tumor phenotype following the combined treatment. CONCLUSION: This work is the first to demonstrate in vitro as in vivo the radio-sensitizing effect of MRTX1257, a potent KRASG12C inhibitor compatible with oral administration, in CT26 KRASG12C mutated cell lines and tumors. This is a first step towards the use of new combinatorial strategies using KRAS inhibitors and RT in KRASG12C mutated tumors, which are the most represented in NSCLC with 14% of patients harboring this mutational profile.

Exploiting epigenetic vulnerabilities in solid tumors: Novel therapeutic opportunities in the treatment of SWI/SNF-defective cancers.

Mammalian switch/sucrose non-fermentable (mSWI/SNF) family complexes are pivotal elements of the chromatin remodeling machinery, which contribute to the regulation of several major cellular functions. Large-scale exome-wide sequencing studies have identified mutations in genes encoding mSWI/SNF subunits in 20% of all human cancers, establishing mSWI/SNF deficiency as a recurrent oncogenic alteration. Accumulating evidence now supports that several mSWI/SNF defects represent targetable vulnerabilities in cancer; notably, recent research advances have unveiled unexpected synthetic lethal opportunities that foster the development of novel biomarker-driven and mechanism-based therapeutic approaches for the treatment of mSWI/SNF-deficient tumors. Here, we review the latest breakthroughs and discoveries that inform our understanding of the mSWI/SNF complexes biology in carcinogenesis, and discuss the most promising therapeutic strategies to target mSWI/SNF defects in human solid malignancies.

Translational Frontiers and Clinical Opportunities of Immunologically Fitted Radiotherapy.

Ionizing radiation can have a wide range of impacts on tumor-immune interactions, which are being studied with the greatest interest and at an accelerating pace by the medical community. Despite its undeniable immunostimulatory potential, it clearly appears that radiotherapy as it is prescribed and delivered nowadays often alters the host's immunity toward a suboptimal state. This may impair the full recovery of a sustained and efficient antitumor immunosurveillance posttreatment. An emerging concept is arising from this awareness and consists of reconsidering the way of designing radiation treatment planning, notably by taking into account the individualized risks of deleterious radio-induced immune alteration that can be deciphered from the planned beam trajectory through lymphocyte-rich organs. In this review, we critically appraise key aspects to consider while planning immunologically fitted radiotherapy, including the challenges linked to the identification of new dose constraints to immune-rich structures. We also discuss how pharmacologic immunomodulation could be advantageously used in combination with radiotherapy to compensate for the radio-induced loss, for example, with (i) agonists of interleukin (IL)2, IL4, IL7, IL9, IL15, or IL21, similarly to G-CSF being used for the prophylaxis of severe chemo-induced neutropenia, or with (ii) myeloid-derived suppressive cell blockers.

Artificial intelligence in oncology: ensuring safe and effective integration of language models in clinical practice.

In this Personal View, we address the latest advancements in automatic text analysis with artificial intelligence (AI) in medicine, with a focus on its implications in aiding treatment decisions in medical oncology. Acknowledging that a majority of hospital medical content is embedded in narrative format, natural language processing has become one of the most dynamic research fields for developing clinical decision support tools. In addition, large language models have recently reached unprecedented performance, notably when answering medical questions. Emerging applications include prognosis estimation, treatment recommendations, multidisciplinary tumor board recommendations and matching patients to recruiting clinical trials. Altogether, we advocate for a forward-looking approach in which the community efficiently initiates global prospective clinical evaluations of promising AI-based decision support systems. Such assessments will be essential to validate and evaluate potential biases, ensuring these innovations can be effectively and safely translated into practical tools for oncological practice. We are at a pivotal moment, where continued advancements in patient care must be pursued with scientific rigor.

Management of Pain Medication in Patients With a History of Bariatric Surgery: A Systematic Review.

CONTEXT: Obesity prevalence is persistently increasing worldwide. Among surgical therapeutic procedures, bypass surgery and sleeve gastrectomy have shown the best results regarding weight loss, prevention, and treatment of secondary complications. However, these surgeries are associated with an increased risk of malabsorption and metabolic changes that could further affect the pharmacokinetics of drugs. On the other hand, patients with a history of such surgeries are more likely to experience pain and request analgesic initiation or adaptation. The question of how to manage pain medication in these patients is challenging due to their narrow therapeutic indexes. OBJECTIVES: To summarize the current literature on the impact of bariatric surgery on the subsequent pharmacokinetics of analgesics and propose a multidisciplinary therapeutic attitude to optimize pain management in these patients. METHODS: We conducted a systematic review that included all pharmacological studies published after 2000. RESULTS: Unexpectedly, these surgeries seem to increase the bioavailability of drugs by long-term improvement of hepatic function. Yet, the medical community drastically lacks robust guidelines for pain management in those patients. This systematic review aims to bring together pharmacological studies related to the use of pain treatments in patients who underwent bypass surgery or sleeve gastrectomy. CONCLUSIONS: Caution should be exercised regarding the risk of overdose in every circumstance: treatment initiation, change of doses, or change of molecule. More prospective trials comparing the pharmacokinetics of medications in obese patients with and without prior bariatric surgery are needed.

LymphoDose: a lymphocyte dose estimation framework-application to brain radiotherapy.

Objective. Severe radiation-induced lymphopenia occurs in 40% of patients treated for primary brain tumors and is an independent risk factor of poor survival outcomes. We developed anin-silicoframework that estimates the radiation doses received by lymphocytes during volumetric modulated arc therapy brain irradiation.Approach. We implemented a simulation consisting of two interconnected compartmental models describing the slow recirculation of lymphocytes between lymphoid organs (M1) and the bloodstream (M2). We used dosimetry data from 33 patients treated with chemo-radiation for glioblastoma to compare three cases of the model, corresponding to different physical and biological scenarios: (H1) lymphocytes circulation only in the bloodstream i.e. circulation inM2only; (H2) lymphocytes recirculation between lymphoid organs i.e. circulation inM1andM2interconnected; (H3) lymphocytes recirculation between lymphoid organs and deep-learning computed out-of-field (OOF) dose to head and neck (H&N) lymphoid structures. A sensitivity analysis of the model's parameters was also performed.Main results. For H1, H2 and H3 cases respectively, the irradiated fraction of lymphocytes was 99.8 ± 0.7%, 40.4 ± 10.2% et 97.6 ± 2.5%, and the average dose to irradiated pool was 309.9 ± 74.7 mGy, 52.6 ± 21.1 mGy and 265.6 ± 48.5 mGy. The recirculation process considered in the H2 case implied that irradiated lymphocytes were irradiated in the field only 1.58 ± 0.91 times on average after treatment. The OOF irradiation of H&N lymphoid structures considered in H3 was an important contribution to lymphocytes dose. In all cases, the estimated doses are low compared with lymphocytes radiosensitivity, and other mechanisms could explain high prevalence of RIL in patients with brain tumors.Significance. Our framework is the first to take into account OOF doses and recirculation in lymphocyte dose assessment during brain irradiation. Our results demonstrate the need to clarify the indirect effects of irradiation on lymphopenia, in order to potentiate the combination of radio-immunotherapy or the abscopal effect.

Enhancing radioprotection: A chitosan-based chelating polymer is a versatile radioprotective agent for prophylactic and therapeutic interventions against radionuclide contamination.

To mitigate the risk of radioactive isotope dissemination, the development of preventative and curative measures is of particular interest. For mass treatment, the developed solution must be easily administered, preferably orally, with effective, nontoxic decorporating properties against a wide range of radioactive isotopes. Currently, most orally administered chelation therapy products are quickly absorbed into the blood circulation, where chelation of the radioactive isotope is a race against time due to the short circulation half-life of the therapeutic. This report presents an alternative therapeutic approach by using a functionalized chitosan (chitosan@DOTAGA) with chelating properties that remains within the gastrointestinal tract and is eliminated in feces, that can protect against ingested radioactive isotopes. The polymer shows important in vitro chelation properties towards different metallic cations of importance, including (Cs(I), Ir(III), Th(IV), Tl(I), Sr(II), U(VI) and Co(II)), at different pH (from 1 to 7) representing the different environments in the gastrointestinal tract. An in vivo proof of concept is presented on a rodent model of uranium contamination following an oral administration of Chitosan@DOTAGA. The polymer partially prevents the accumulation of uranium within the kidneys (providing a protective effect) and completely prevents its uptake by the spleen.

Theragnostic Gadolinium-Based Nanoparticles Safely Augment X-ray Radiation Effects in Patients with Cervical Cancer.

Activated guided irradiation by X-ray (AGuIX) nanoparticles are gadolinium-based agents that have the dual benefit of mimicking the effects of a magnetic resonance imaging (MRI) contrast agent used in a clinical routine and enhancing the radiotherapeutic activity of conventional X-rays (for cancer treatment). This "theragnostic" action is explained on the one hand by the paramagnetic properties of gadolinium and on the other hand by the generation of high densities of secondary radiation following the interaction of ionizing radiation and high-Z atoms, which leads to enhanced radiation dose deposits within the tumors where the nanoparticles accumulate. Here, we report the results of a phase I trial that aimed to assess the safety and determine the optimal dose of AGuIX nanoparticles in combination with chemoradiation and brachytherapy in patients with locally advanced cervical cancer. AGuIX nanoparticles were administered intravenously and appropriately accumulated within tumors on a dose-dependent manner, as assessed by T1-weighted MRI, with a rapid urinary clearance of uncaught nanoparticles. We show that the observed tumor accumulation of the compounds can support precise delineation of functional target volumes at the time of brachytherapy based on gadolinium enhancement. AGuIX nanoparticles combined with chemoradiation appeared well tolerated among the 12 patients treated, with no dose-limiting toxicity observed. Treatment yielded excellent local control, with all patients achieving complete remission of the primary tumor. One patient had a distant tumor recurrence. These results demonstrate the clinical feasibility of using theranostic nanoparticles to augment the accuracy of MRI-based treatments while focally enhancing the radiation activity in tumors.

Radiotherapy as a means to increase the efficacy of T-cell therapy in solid tumors.

Chimeric antigen receptor (CAR)-T cells have demonstrated significant improvements in the treatment of refractory B-cell malignancies that previously showed limited survival. In contrast, early-phase clinical studies targeting solid tumors have been disappointing. This may be due to both a lack of specific and homogeneously expressed targets at the surface of tumor cells, as well as intrinsic properties of the solid tumor microenvironment that limit homing and activation of adoptive T cells. Faced with these antagonistic conditions, radiotherapy (RT) has the potential to change the overall tumor landscape, from depleting tumor cells to reshaping the tumor microenvironment. In this article, we describe the current landscape and discuss how RT may play a pivotal role for enhancing the efficacy of adoptive T-cell therapies in solid tumors. Indeed, by improving homing, expansion and activation of infused T cells while reducing tumor volume and heterogeneity, the use of RT could help the implementation of engineered T cells in the treatment of solid tumors.

Radio-induced lymphopenia in the era of anti-cancer immunotherapy.

Radiation-induced lymphopenia (RIL) is characterized by a significant decrease in the absolute number of lymphocytes circulating in the blood after radiotherapy. With the major shift in cancer management initiated by cancer immunotherapy (IT), the reduction of incidence of RIL appears today as an extremely promising way of potentiating the synergy between radiotherapy and immunotherapy. However, the causes of RIL and mechanisms involved are still poorly understood. Improving our knowledge on RIL is therefore essential to limit it and thus improve the quality of care delivered to patients. The objective of this review is to provide a global view of RIL from a clinical point of view, with particular emphasis on recent knowledge and avenues explored to explain RIL and especially its depletion and remission kinetics. An opening on treatment concepts to be rethought is conducted in the context of combined RT/IT treatments.

Practice changing data and emerging concepts from recent radiation therapy randomised clinical trials.

INTRODUCTION: Oncology treatments are constantly and rapidly evolving. We aimed at highlighting the latest radiation therapy practice changing trials and emerging concepts, through an overview of recent randomised clinical trials (RCTs). MATERIALS AND METHODS: Requests were performed in the Medline database to identify all publications reporting radiation therapy RCTs from 2018 to 2021. RESULTS: Recent RCTs sustained the role of newer combinatorial strategies through radioimmunotherapy for early stage or metastatic lung cancer, newer pro-apoptotic agents (e.g. debio 1143 in locoregionally advanced head and neck squamous cell carcinoma) or nanoparticles (e.g. NBTXR3 in locally advanced soft-tissue sarcoma). High-tech radiotherapy allows intensifying treatments and gaining ground in some indications through the development of stereotactic body radiotherapy for example. First randomised evidence on personalised radiation therapy through imaging-based (18FDG positron emission tomography-computed tomography for lung cancer or early stage unfavourable Hodgkin lymphoma, PMSA positron emission tomography-computed tomography or magnetic resonance imaging for high-risk prostate cancer) or biological biomarkers (PSA for prostate cancer, HPV for head and neck cancer, etc) were conducted to more tailored treatments, with more favourable outcomes. Patients' quality of life and satisfaction appeared to be increasing aims. RCTs have validated (ultra)hypofractionated schemes in many indications as for breast, prostate or rectal cancer, resulting in equivalent outcomes and toxicities, more convenient for patients and favouring shared decision making. CONCLUSION: Radiation therapy is a dynamic field of research, and many RCTs have greatly impacted therapeutic standards over the last years. Investments in radiotherapy research should facilitate the transfer of innovation to clinic.

Prognostic value of tumor immune biomarkers in biopsies from patients with refractory solid cancers.

PD-L1 and tumor-infiltrating lymphocytes play a key role in the immune escape of cancer, although their prognostic value remains unknown in patients with refractory solid cancer compared to other known prognostic estimation methods. In this ancillary study, we assessed the prognostic value of previously-defined prognostic scores (such as the Royal Marsden Hospital (RMH) score) and of PD-L1, CD3, CD8 and FOXP3 expressions based on immunohistochemistry (IHC) and RNA sequencing (RNAseq) of tumor samples from patients included in the personalized-medicine MOSCATO-02 trial. We collected biopsies with successful IHC analysis from 266 patients treated between April 2016 and September 2017, among whom 170 (63.9%) also had a matched RNAseq. We used a Random Forest model to identify the best prognostic factor, and a Lasso-penalized Cox model to validate the findings. We found that the RMH score was the strongest prognostic factor, with high scores associated with a higher risk of death (Hazard Ratio (HR)=1.29; CI95%[1.19-1.21]). The PD-L1 expression score obtained from IHC analyses was the second-best performing predictor, with the 1+ score (low expression) linked to a lower risk of death (HR=0.564; CI95%[0.539-0.580]). Other tested variables, including primary tumor type and subsequent treatments received following biopsy, were not found significantly linked to prognosis. We found modest correlation between IHC and RNAseq expressions of immune genes, but RNAseq related better to prognosis. Overall, our study supports the use of the RMH score and the assessment of PD-L1 expression in IHC to estimate prognosis in patients with advanced cancer.

Epigenetic gene alterations in metastatic solid tumours: results from the prospective precision medicine MOSCATO and MATCH-R trials.

INTRODUCTION: Although the role of epigenetic alterations in oncogenesis has been well studied, their prevalence in metastatic solid tumours is still poorly described. We therefore aimed at: (i) describing the presence of epigenetic gene alterations (EGA) - defined by an alteration in a gene encoding an epigenetic regulator; and (ii) evaluating their relationship with clinical characteristics and outcome in patients (pts) included in prospective molecular profiling trials. MATERIALS AND METHODS: On-purpose tumour biopsies from pts with metastatic solid tumours enrolled in the Gustave Roussy-sponsored MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials were molecularly profiled using whole exome sequencing (WES). Alterations in 176 epigenetic genes were assessed and classified as pathogenic variants (PV) or non-pathogenic variants by a molecular tumour board. Clinical characteristics and outcome were collected. RESULTS: Between Dec 2011 and Oct 2016, WES was successfully performed in 292 pts presenting various solid tumours. We found 496 epigenetic gene alterations in 134 patients (49%), including 237 pathogenic variants in 86 patients; 63 tumour samples (47%) presented ≥3 EGAs. The median number of previous treatment lines was 3 (1-10). The most frequently altered genes were KMT2D and KMT2C (16% each), ARID1A and SETD2 (10% each) and KMT2A (8%).; 31% of EGA co-occurred with a driver gene alteration (p < 0.001). Outcome was not correlated with the presence of EGA. CONCLUSIONS: Epigenetic alterations occur frequently in metastatic solid tumours. With the current development of epigenetic modifiers, they increasingly represent actionable targets. Such genes should now be systematically analysed in molecular profiling studies.

Applications of single-cell and bulk RNA sequencing in onco-immunology.

The rising interest for precise characterization of the tumour immune contexture has recently brought forward the high potential of RNA sequencing (RNA-seq) in identifying molecular mechanisms engaged in the response to immunotherapy. In this review, we provide an overview of the major principles of single-cell and conventional (bulk) RNA-seq applied to onco-immunology. We describe standard preprocessing and statistical analyses of data obtained from such techniques and highlight some computational challenges relative to the sequencing of individual cells. We notably provide examples of gene expression analyses such as differential expression analysis, dimensionality reduction, clustering and enrichment analysis. Additionally, we used public data sets to exemplify how deconvolution algorithms can identify and quantify multiple immune subpopulations from either bulk or single-cell RNA-seq. We give examples of machine and deep learning models used to predict patient outcomes and treatment effect from high-dimensional data. Finally, we balance the strengths and weaknesses of single-cell and bulk RNA-seq regarding their applications in the clinic.

PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer.

Inactivation of Polybromo 1 (PBRM1), a specific subunit of the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% of clear cell renal cell carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used a series of orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with PBRM1 deficiency. The PBRM1/PARP inhibitor synthetic lethality was recapitulated using several clinical PARP inhibitors in a series of in vitro model systems and in vivo in a xenograft model of ccRCC. In the absence of exogenous DNA damage, PBRM1-defective cells exhibited elevated levels of replication stress, micronuclei, and R-loops. PARP inhibitor exposure exacerbated these phenotypes. Quantitative mass spectrometry revealed that multiple R-loop processing factors were downregulated in PBRM1-defective tumor cells. Exogenous expression of the R-loop resolution enzyme RNase H1 reversed the sensitivity of PBRM1-deficient cells to PARP inhibitors, suggesting that excessive levels of R-loops could be a cause of this synthetic lethality. PARP and ATR inhibitors also induced cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) innate immune signaling in PBRM1-defective tumor cells. Overall, these findings provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers. SIGNIFICANCE: This study demonstrates that PARP and ATR inhibitors are synthetic lethal with the loss of PBRM1, a PBAF-specific subunit, thus providing the rationale for assessing these inhibitors in patients with PBRM1-defective cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/2888/F1.large.jpg.

Combining epigenetic drugs with other therapies for solid tumours - past lessons and future promise.

Epigenetic dysregulation has long been recognized as a key factor contributing to tumorigenesis and tumour maintenance that can influence all of the recognized hallmarks of cancer. Despite regulatory approvals for the treatment of certain haematological malignancies, the efficacy of the first generation of epigenetic drugs (epi-drugs) in patients with solid tumours has been disappointing; however, successes have now been achieved in selected solid tumour subtypes, thanks to the development of novel compounds and a better understanding of cancer biology that have enabled precision medicine approaches. Several lines of evidence support that, beyond their potential as monotherapies, epigenetic drugs could have important roles in synergy with other anticancer therapies or in reversing acquired therapy resistance. Herein, we review the mechanisms by which epi-drugs can modulate the sensitivity of cancer cells to other forms of anticancer therapy, including chemotherapy, radiation therapy, hormone therapy, molecularly targeted therapy and immunotherapy. We provide a critical appraisal of the preclinical rationale, completed clinical studies and ongoing clinical trials relating to combination therapies incorporating epi-drugs. Finally, we propose and discuss rational clinical trial designs and drug development strategies, considering key factors including patient selection, tumour biomarker evaluation, drug scheduling and response assessment and study end points, with the aim of optimizing the development of such combinations.

PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.

The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations.

DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade.

Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. Excision repair cross-complementation group 1 (ERCC1) deficiency is frequently found in non-small-cell lung cancer (NSCLC), making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in the disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house-generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). We also found reduced NAMPT expression in NSCLC samples with low levels of ERCC1. These metabolic alterations were a primary effect of ERCC1 deficiency, and caused selective exquisite sensitivity to small-molecule NAMPT inhibitors, both in vitro - ERCC1-deficient cells being approximately 1,000 times more sensitive than ERCC1-WT cells - and in vivo. Using transmission electronic microscopy and functional metabolic studies, we found that ERCC1-deficient cells harbor mitochondrial defects. We propose a model where NAD+ acts as a regulator of ERCC1-deficient NSCLC cell fitness. These findings open therapeutic opportunities that exploit a yet-undescribed nuclear-mitochondrial synthetic lethal relationship in NSCLC models, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy.

Otorhinolaryngological Toxicities of New Drugs in Oncology.

Many new or relatively new cancer drugs-personalized anticancer agents-have been approved for use in various clinical settings in oncology or are still under evaluation in clinical trials. Targeted therapies as well as new immune checkpoint blockers have toxicity profiles that differ from conventional cytotoxic chemotherapy, and many can cause adverse effects that affect the mouth and pharynx, the nasal cavities, and the larynx. This review aims to provide an overview of current knowledge concerning these side effects and contemporary management. Adverse effects of the mouth/pharynx, nasal cavities, larynx, and cochlear-vestibular system are generally low grade (according to the Common Terminology Criteria for Adverse Events) and generally present non-life-threatening symptoms. However, the impact on patients' quality of life could be important. The incidence and severity vary according to the drug, its target(s), and dose, but there are currently no known predictive factors, and each patient has an individual toxicity profile. Management guidelines are based on expert opinion. These ear, nose, and throat adverse effects are not frequently mentioned in the literature because of the often non-specific nature of the symptoms and their mildness, but also the absence of specific treatment. These symptoms can contribute to decreased quality of life and lead to drug compliance issues if not diagnosed and managed appropriately.