Microenvironment shapes small-cell lung cancer neuroendocrine states and presents therapeutic opportunities.

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states.

Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial.

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

The dark side of circular RNA, a new driver of genome instability.

Circular RNAs (circRNAs) are covalently closed RNA molecules whose functions are still largely uncharacterized. In the July issue of Cancer Cell, Conn et al.1 demonstrate that circRNA can bind cognate DNA loci, forming circRNA-DNA hybrids (circR loops), driving genetic rearrangements of MLL/KMT2A, which are associated with the most aggressive acute leukemias.

ATR inhibition augments the efficacy of lurbinectedin in small-cell lung cancer.

Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC-driven non-neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high-throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First-in-class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S-phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC-driven non-neuroendocrine tumors which are resistant to first-line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin-berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.

Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial.

PURPOSE: Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations. PATIENTS AND METHODS: In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels. RESULTS: Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer. CONCLUSIONS: ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557.

Elevated HDAC activity and altered histone phospho-acetylation confer acquired radio-resistant phenotype to breast cancer cells.

BACKGROUND: Poor-responsiveness of tumors to radiotherapy is a major clinical problem. Owing to the dynamic nature of the epigenome, the identification and targeting of potential epigenetic modifiers may be helpful to curb radio-resistance. This requires a detailed exploration of the epigenetic changes that occur during the acquirement of radio-resistance. Such an understanding can be applied for effective utilization of treatment adjuncts to enhance the efficacy of radiotherapy and reduce the incidence of tumor recurrence. RESULTS: This study explored the epigenetic alterations that occur during the acquirement of radio-resistance. Sequential irradiation of MCF7 breast cancer cell line up to 20 Gy generated a radio-resistant model. Micrococcal nuclease digestion demonstrated the presence of compact chromatin architecture coupled with decreased levels of histone PTMs H3K9ac, H3K27 ac, and H3S10pK14ac in the G0/G1 and mitotic cell cycle phases of the radio-resistant cells. Further investigation revealed that the radio-resistant population possessed high HDAC and low HAT activity, thus making them suitable candidates for HDAC inhibitor-based radio-sensitization. Treatment of radio-resistant cells with HDAC inhibitor valproic acid led to the retention of γH2AX and decreased H3S10p after irradiation. Additionally, an analysis of 38 human patient samples obtained from 8 different tumor types showed variable tumor HDAC activity, thus demonstrating inter-tumoral epigenetic heterogeneity in a patient population. CONCLUSION: The study revealed that an imbalance of HAT and HDAC activities led to the loss of site-specific histone acetylation and chromatin compaction as breast cancer cells acquired radio-resistance. Due to variation in the tumor HDAC activity among patients, our report suggests performing a prior assessment of the tumor epigenome to maximize the benefit of HDAC inhibitor-based radio-sensitization.

Lead sorption onto acrylamide modified titanium nanocomposite from aqueous media.

The purpose of this study was to investigate the adsorption of lead (Pb(II)) onto acrylamide (AM) doped TiO2 nanocomposites (Ti-AM) using batch techniques for evaluation of isothermal and kinetic properties. Chemical, structural and textural characteristics of the material were determined by FTIR, XPS, XRD, SEM and EDAX analysis. XPS results showed that a change in oxidation state occurred due to lead adsorption. The adsorption conditions for the adsorbent were optimized by varying several experimental parameters, i.e., contact time, initial lead concentration, adsorbent dose, pH, and electrolyte amount of the solution. The adsorption data were modeled using both the Langmuir and Freundlich isotherms. The maximum adsorption capacity using Langmuir isotherm (qmax) for the nanocomposite was found to be 476.19 mg g(-1). Adsorption showed pseudo-second-order kinetics with a rate constant of 8.7 × 10(-4) and 1.2 × 10(-4) g mg(-1)min(-1) at 100 and 500 mg L(-1) initial Pb(II) concentrations, respectively. Acrylamide concentration in nanocomposite synthesis up to 1 g had greater influence on the sorption of lead. The most favorable pH for the adsorption was pH 5.5. With increasing concentrations of three electrolytes (NaCl, Na2SO4 and Na2CO3) from 0.01 to 1.0 M Pb(II), the lead removal decreases from 76.3 to 32.8 mg g(-1), from 97.4 to 68.7 mg g(-1), and from 98.8 to 72.5 mg g(-1), respectively. Further, the Ti-AM nanocomposite is amenable to efficient regeneration by a 0.05 N HCl solution for repeated (up to six cycles) use without any significant capacity loss, making this approach very economical.

Poly(acrylamide) functionalized chitosan: an efficient adsorbent for azo dyes from aqueous solutions.

In the present communication we report on the optimization of persulfate/ascorbic acid initiated synthesis of chitosan-graft-poly(acrylamide) (Ch-g-PAM) and its application in the removal of azo dyes. The optimum yield of the copolymer was obtained using 16 x 10(-2)M acrylamide, 3.0 x 10(-2)M ascorbic acid, 2.4 x 10(-3)M K(2)S(2)O(8) and 0.1g chitosan in 25 mL of 5% aqueous formic acid at 45+/-0.2 degrees C. Ch-g-PAM remained water insoluble even under highly acidic conditions and could efficiently remove Remazol violet and Procion yellow dyes from the aqueous solutions over a pH range of 3-8 in contrast to chitosan (Ch) which showed pH dependent adsorption. The adsorption data of the Ch-g-PAM and Ch for both the dyes were modeled by Langmuir and Freundlich isotherms where the data fitted better to Langmuir isotherms. To understand the adsorption behavior of Ch-g-PAM, adsorption of Remazol violet on to the copolymer was optimized and the kinetic and thermodynamic studies were carried out taking Ch as reference. Both Ch-g-PAM and Ch followed pseudo-second-order adsorption kinetics. The thermodynamic study revealed a positive heat of adsorption (Delta H degrees), a positive DeltaS degrees and a negative Delta G degrees, indicating spontaneous and endothermic nature of the adsorption of RV dye on to the Ch-g-PAM. The Ch-g-PAM was found to be very efficient in removing color from real industrial wastewater as well, though the interfering ions present in the wastewater slightly hindered its adsorption capacity. The data from regeneration efficiencies for ten cycles evidenced the high reusability of the copolymer in the treatment of waste water laden with even high concentrations of dye.

Contamination of nitrate and fluoride in ground water along the Ganges Alluvial Plain of Kanpur district, Uttar Pradesh, India.

Nitrate-N and Fluoride concentrations were analyzed in shallow and unconfined ground water aquifers of Kanpur district along the Ganges Alluvial Plain of Northern India. Kanpur district was divided into three zones namely, Bithore, Kanpur City and Beyond Jajmau and sampling was carried out three seasons (summer, monsoon and winter). The data set consisted of the results of water samples from around 99 India Mark II hand Pumps, which were analyzed for summer monsoon and winter seasons. In Bithore zone, 19% of the samples exceeded the BIS (Bureau of India Standards) limit 10.2 mg/l as nitrate-N and as high as 166 mg/l as nitrate-N was observed. 10% and 7% samples in Kanpur city and beyond Jajmau zone respectively, exceeded the BIS limit. The Frequency distribution histogram of nitrate-N revealed a skewed (non-normal) distribution. Both point and non-point sources contribute to the ground water contamination. Especially in Bithore zone, the point sources could be attributed to the animal wastes derived from cows and buffaloes and non point sources could be due to the extensive agricultural activity prevalent in that area. Fluoride concentration in most samples was within the BIS maximum permissible level of 1.5 mg/l. No significant seasonal variation in water quality parameters was observed.

Removal of lead from aqueous solutions using Cassia grandis seed gum-graft-poly(methylmethacrylate).

Using persulfate/ascorbic acid redox system, a series of Cassia grandis seed gum-graft-poly(methylmethacrylate) samples were synthesized. The copolymer samples were evaluated for lead(II) removal from the aqueous solutions where the sorption capacities were found proportional to the grafting extent. The conditions for the sorption were optimized using copolymer sample of highest percent grafting. The sorption was found pH and concentration dependent, pH 2.0 being the optimum value. Adsorption of lead by the grafted seed gum followed a pseudo-second-order kinetics with a rate constant of 4.64 x 10(-5) g/mg/min. The equilibrium data followed the Langmuir isotherm model with maximum sorption capacity of 126.58 mg/g. The influence of electrolytes NaCl, Na(2)SO(4) on lead uptake was also studied. Desorption with 2 N HCl could elute 76% of the lead ions from the lead-loaded copolymer. The regeneration experiments revealed that the copolymer could be successfully reused for at least four cycles though there was a successive loss in lead sorption capacity with every cycle. The adsorbent was also evaluated for Pb(II) removal from battery waste-water containing 2166 mg/L Pb(II). From 1000 times diluted waste water, 86.1% Pb(II) could be removed using 0.05 g/20 ml adsorbent dose, while 0.5 g/20 ml adsorbent dose was capable of removing 60.29% Pb from 10 times diluted waste water. Optimum Pb(II) binding under highly acidic conditions indicated that there was a significant contribution of nonelectrostatic interactions in the adsorption process. A possible mechanism for the adsorption has been discussed.

Novel chitosan derivative for the removal of cadmium in the presence of cyanide from electroplating wastewater.

Chitosan was chemically modified by introducing xanthate group onto its backbone using carbondisulfide under alkaline conditions. The chemically modified chitosan flakes (CMC) was used as an adsorbent for the removal of cadmium ions from electroplating waste effluent under laboratory conditions. CMC was found to be far more efficient than the conventionally used adsorbent activated carbon. The maximum uptake of cadmium by CMC in batch studies was found to be 357.14 mg/g at an optimum pH of 8.0 whereas for plain chitosan flakes it was 85.47 mg/g. Since electroplating wastewater contains cyanide in appreciable concentrations, interference of cyanide ions in cadmium adsorption was found to be very significant. This problem could be easily overcome by using higher doses of CMC, however, activated carbon was not found to be effective even at higher doses. Due to the high formation constant of cadmium with xanthate and adsorption was carried out at pH 8, cations like Pb(II), Cu(II), Ni(II) and Zn(II) did not interfere in the adsorption. Dynamics of the sorption process were studied and the values of rate constant of adsorption were calculated. Desorption of the bound cadmium from CMC was accomplished with 0.01 N H(2)SO(4). The data from regeneration efficiencies for 10 cycles evidenced the reusability of CMC in the treatment of cadmium-laden wastewater.