bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 208: Peposertib-induced senescence primes irradiated p53 wild-type cancer cells for clearance by both immune cells and senolytic drugs
Authors: Carr Michael , Sun Qing , Lee Chien-Fei , Zenke Frank T. , Blaukat Andree , Vassilev Lyubomir T. 
Published: June 2022

Abstract
Peposertib (previously known as M3814) is a potent and selective DNA-PK inhibitor in early-stage clinical development. It effectively blocks the non-homologous end-joining pathway for repair of DNA double-strand breaks (DSB) and has shown strong synergy with ionizing radiation (IR) and DSB-inducing chemotherapy. We recently reported that M3814 overactivates the ATM/p53 signaling axis, reinforces cell cycle checkpoint arrest, and promotes durable premature senescence in irradiated p53 wild-type cancer cells. This unique property of peposertib permits to turn the bulk of irradiated cancer cells into nearly uniform senescent cell population. Using this experimental model, we examined the immunological effects and potential therapeutic applications of IR+peposertib induced senescence. Gene expression analyses of IR+peposertib treated A549 cells showed activation of multiple immune-related genes in the senescent cells, consistent with a strong STING-driven inflammatory response. Multiple secreted cytokines were found substantially elevated in culture media compared to IR controls. Co-culture of IR+peposertib induced senescent cells with PBMCs from healthy volunteers coupled with FACS analyses and live imaging revealed stimulation of the T-cell compartment and killing of senescent but not control cells. Further co-culture experiments with isolated NK cells showed accelerated killing of the senescent IR+peposertib treated A549 cells as compared to controls. These results indicated that IR+peposertib induced inflammatory signaling in senescent A549 cells can stimulate an immune response in vitro, resulting in the effective elimination of both treated and naive A549 cells. We also explored a pharmacological "two-hit" approach. Viability assays and time-lapse imaging showed that the senescent, IR+peposertib treated A549 cells were sensitive to several reported senolytic agents. Of those, the BCL-XL inhibitor A-1331852 was most effective at killing peposertib-promoted senescent A549 cells. Our experiments revealed that selective inhibition of DNA-PK in irradiated p53 wild-type cancer cells provides a powerful mechanism for induction of senescent cancer cells with an immunostimulatory secretory phenotype in vitro. In addition, these cells can be selectively targeted by senolytic agents, suggesting that triple combination radiotherapy with DNA-PK inhibitors and senolytics could offer a potential new approach to the treatment of locally advanced tumors.
Citation Format: Michael Carr, Qing Sun, Chien-Fei Lee, Frank T. Zenke, Andree Blaukat, Lyubomir T. Vassilev. Peposertib-induced senescence primes irradiated p53 wild-type cancer cells for clearance by both immune cells and senolytic drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 208.
Abstract 2081: Poly ADP-ribose polymerase inhibition enhances T cell cytotoxicity and anti-tumor function by altering NAD+ levels
Authors: Dean Matthew J. , Zheng Liqin , Philbrook Phaethon , Ochoa Augusto C. , Boulares A. Hamid 
Published: June 2022

Abstract
Poly ADP-ribose polymerase (PARP) is an NAD-dependent DNA repair enzyme. Inhibition of PARP in BRCA-mutant cancers has been a clinically approved therapy for several years. While the PARP inhibitor, olaparib, has been approved for the treatment of BRCA-mutant breast and ovarian cancers, it has not been used in other cancers because its mechanism of action relies on synthetic lethality. We have found that olaparib may also have use in other cancers due to its ability to modulate the immune system directly. Specifically, we have found that olaparib is able to increase the proliferation, activation, and cytotoxicity of T cells in vitro and reduce tumor growth in vivo at low doses. Recent papers have proposed that olaparib is able to enhance T cell function through the stimulator of interferon genes (STING) pathway by enhancing antigen presenting cell activity and resulting in more granzyme B expression and enhanced tumor killing. Using purified T cells from both wild type and STING knockout mice, we have shown that olaparib can also cause an increase in granzyme B and perforin expression, an increase in T cell proliferation, and enhanced tumor cell killing in a STING-independent manner. Because PARP is an NAD-consuming enzyme, we examined the role of NAD+ in the activation T cells and the production of granzyme B and perforin. By using an inhibitor of NAD+ recycling, FK866, we show that T cells have reduced NAD+ levels, reduced granzyme B and perforin expression, and even fail to activate in the presence of CD3 and CD28 when NAD+ is limited; however, adding olaparib to these cells rescues the effects of FK866 and allows proliferation and granzyme B production. In vivo we can see that even at olaparib doses that are significantly below those which induce synthetic lethality of tumor cells, olaparib is able to inhibit tumor growth in models of both colorectal and breast cancer. This suggests that olaparib can modulate the activity of T cells directly and has implications for enhancing the anti-tumor activity of these cells both alone and in combination with other forms of immunotherapy.
Citation Format: Matthew J. Dean, Liqin Zheng, Phaethon Philbrook, Augusto C. Ochoa, A. Hamid Boulares. Poly ADP-ribose polymerase inhibition enhances T cell cytotoxicity and anti-tumor function by altering NAD+ levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2081.
Abstract 2095: Selective inhibition of the STAT3 pathway suppresses K-ras mutant lung tumorigenesis
Authors: Clowers Michael J. , Chou Cody , Yuan Bo , Velasco Walter V. , Zarghooni Melody , Peng Stephen , Eckols T Kris , Kadara Humam , Tweardy David J. , Moghaddam Seyed Javad 
Published: June 2022

Abstract
K-ras mutant lung adenocarcinoma (KM-LUAD) is a difficult-to-drug cancer subtype characterized by a chronic inflammatory tumor microenvironment (TME). Resistance to therapies, including immune checkpoint blockade (ICB), necessitates therapies that target this inflammatory TME. A major transcription factor that mediates chronic inflammation in KM-LUAD is signal transducer and activator of transcription 3 (STAT3). Inhibiting STAT3 may attenuate pro-tumor inflammation. Moreover, STAT3 modulates PD-L1 transcription, so STAT3 inhibitors in conjunction with ICB may increase ICB response rates. Here, we tested the anti-tumor ability of TTI-101, a selective STAT3 inhibitor, in a STAT3 addicted lung cancer cell line (MDA-F471) and in a transgenic mouse model of KM-LUAD (CCSPCre/LSL-KrasG12D, CC-LR). For in vivo experiments, CC-LR mice were treated daily with 50 mg/kg TTI-101 by oral gavage from 10 to 14 weeks of age to model a preventative regimen or from 14 to 18 weeks of age to survey the treatment effect on established tumors. TTI-101 was compared to anti-PD-1 ICB, with 200 μg injected intraperitoneally 3 times per week. In MDA-F471 cells, TTI-101 treatment decreased cell viability, with an IC50 of ~ 20 μM. In mice treated from 10 to 14 weeks of age, TTI-101 therapy significantly reduced the tumor burden compared to ICB. TTI-101 also reduced the number of proliferating cells within tumors. Mice in the 14-18-week group displayed similar trends, but these experiments are ongoing, as are combination TTI-101 and ICB treatment regimens. Our studies show that TTI-101 can reduce K-ras driven tumor cell proliferation in vitro and in vivo, suggesting STAT3 inhibition as an alternative preventive and therapeutic modality for KM-LUAD. The ongoing combination treatments and the 14-18-week cohorts will elucidate the timing of treatments as well as reveal if by targeting the inflammatory TME we are able to improve response to ICB. Funded by: R01 grant from NIH/NCI (R01CA225977)
Citation Format: Michael J. Clowers, Cody Chou, Bo Yuan, Walter V. Velasco, Melody Zarghooni, Stephen Peng, T Kris Eckols, Humam Kadara, David J. Tweardy, Seyed Javad Moghaddam. Selective inhibition of the STAT3 pathway suppresses K-ras mutant lung tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2095.
Abstract 2096: Natural killer cells inhibit CD4+ T cell mediated IL-9 production in head and neck Cancer
Authors: Crist McKenzie , Lehn Maria , Takiar Vinita , Wise-Draper Trisha 
Published: June 2022

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer in the world, yet 5 year survival remains poor for those with recurrence despite advances in treatment such as immunotherapy. Checkpoint blockade substantially improved survival in ~20% of recurrent and/or metastatic HNSCC patients. However, given the lack of efficacy in most patients, and the known immunosuppressive nature of HNSCC, exploring other potential immune cell therapeutic targets is of interest. Decreased natural killer (NK) as well as increased immunosuppressive CD4+ regulatory T cells (Tregs) in both peripheral blood and the tumor microenvironment are associated with a poor prognosis in HNSCC. We discovered that the anti-diabetes drug, metformin, which is also known to improve immune cell function, not only increases peripheral NK cells in HNSCC patients to the level of healthy controls, but also suppresses IL-9 secretion from NK cells. IL-9 has been implicated as a driving factor in allergic disease, a poor prognosis factor in hematologic malignancies, and an enhancer of T-reg immunosuppressive abilities. However, the function of IL-9 in solid tumors is poorly understood. Interestingly, upon depletion of CD56+ NK and NKT cells from peripheral blood mononuclear cells (PBMCs), there was a significant increase of IL-9 secretion. This effect was negated upon depletion of CD4+ T cells suggesting that NK cells may directly or indirectly inhibit CD4+ T cell IL-9 production. In order to understand potential consequences of IL-9 overproduction, we subjected HNSCC cell lines, which we demonstrated express IL9 receptor, to exogenous IL-9 which resulted in enhanced proliferation. We also found that IL-9 plasma levels are high in HNSCC patients compared to healthy controls corroborating a potential tumorigenic role for IL-9. In order to elucidate potential mechanism(s) by which NK/NKT cells regulate CD4+ T cell production, we performed single-cell RNAseq on PBMCs upon NK and NKT cell depletion. We also performed flow cytometry to identify specific CD4+ cell types responsible for increased IL-9 production and the consequential changes in other immune cell phenotypes upon the absence of NK/NKT cells. Understanding the role of IL-9 in HNSCC will be important for utilizing IL-9 as a potential marker for HNSCC prognosis as well as a possible target for future immunotherapy approaches.
Citation Format: McKenzie Crist, Maria Lehn, Vinita Takiar, Trisha Wise-Draper. Natural killer cells inhibit CD4+ T cell mediated IL-9 production in head and neck Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2096.
Abstract 2108: ScRNA-Seq and imaging mass cytometry analyses unveil iNKT cells-mediated anti-tumor immunity in pancreatic tumor liver metastasis
Authors: Wang Jie , Yi Qijun , Liu Tingting , Yao Yi , Loveless Ian , Subedi Kalpana , Adrianto Indra , Crawford Howard , Zhou Li , Mi Qing-Sheng 
Published: June 2022

Abstract
Background: Liver metastasis is a common feature of pancreatic tumor and associated with a poor outcome. Invariant natural killer cells (iNKT) are innate-like T cells that are important regulators of innate and adaptive immune responses in cancer and is the largest subset of lymphocytes within liver. However, the role of iNKT cells in pancreatic tumor liver metastasis (PTLM) is still not clear. Hypothesis: activated liver iNKT cells could play a role in PTLM.
Method: We established a PTLM mouse model by hemi-spleen murine pancreatic tumor cells (CF1242) injection. We combined single-cell RNA sequencing, flow cytometry analysis, and imaging mass cytometry analysis to landscape the immune profile of tumor microenvironment during PTLM with or without iNKT cell activator α-galactosylceramide (αGC) treatment.
Results: αGC treatment significantly blocked PTLM development based on liver weight compared to control group(P&lt;0.001). We sequenced total 6,728 CD45+ infiltrating immune cells in PTLM with/without αGC treatment and identified total 12 immune subpopulations that were present in both samples at different frequencies. Post αGC treatment, activated iNKT cells in liver appeared robust population expansion and enriched in cytotoxic signaling pathway. Alternatively, activated iNKT cells promoted infiltrating CD4 T cells to a Th1 profile shift, and promoted infiltrating CD8 T cells toward an effector/memory phenotype (upregulation of the CD44, T-bet, and IFN-γ; P&lt;0.001), and increased NK cell cytotoxic activity (P&lt;0.001). In addition, we observed that aGC treatment blocked infiltrating CD8 T cell exhaustion by downregulating the immune checkpoint TIGIT, Lag3, and PD-1 (P&lt;0.001). Analysis of tumor-infiltrating myeloid clusters revealed that macrophage skewed to M1 phenotype compared to the control group(P&lt;0.05).
Conclusion: αGC treatment can expand and activate liver iNKT cells, which may directly increase tumor cell killing ability, recruit immune cells to tumor sites, and orchestrate the anti-tumor function through boost both innate and adaptive tumor immunity to inhibit PTLM. Our results indicate that iNKT cells may serve as a new immunotherapeutic target for PTLM. (Funded by HFCI and NIH/NIAID)
Citation Format: Jie Wang, Qijun Yi, Tingting Liu, Yi Yao, Ian Loveless, Kalpana Subedi, Indra Adrianto, Howard Crawford, Li Zhou, Qing-Sheng Mi. ScRNA-Seq and imaging mass cytometry analyses unveil iNKT cells-mediated anti-tumor immunity in pancreatic tumor liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2108.
Abstract 2155: PMR-116, a novel inhibitor of ribosome biogenesis with antitumor activity in preclinical models of prostate cancer
Authors: Huglo Alisee , Rebello Richard , Lawrence Mitchell , Risbridger Gail , Drygin Denis , Haddach Mustapha , Hannan Katherine , Hannan Ross , Furic Luc 
Published: June 2022

Abstract
Advanced prostate cancer is characterised by mutations and amplifications of genes involved in regulating protein synthesis. PTEN-loss stimulates activity of the mTOR pathway, while amplification of MYC leads to increased ribosome biogenesis and elevated mRNA translation rate. Our previous work has demonstrated the efficacy of co-targeting ribosome biogenesis, via inhibition of RNA Pol I activity, and 4E-BP1 phosphorylation to suppress prostate cancer growth in vivo in GEMM of PCa and in patient-derived xenografts (Rebello et al., Clinical Cancer Research, 2016; Lawrence et al., European Urology, 2018).
In a collaboration with Pimera Inc., we investigated the efficacy of their new lead RNA Pol I inhibitor PMR-116 in models of prostate cancer. PMR-116 is well tolerated in vivo in mice and can be given at 300mg/kg weekly. Using the Hi-MYC mouse model of PCa we show that dosing 6 month old mice once weekly for 4 weeks can decrease the incidence of invasive lesions by up to 85% compared to vehicle control while reverting glands to patterns of low grade intraepithelial neoplasia. PMR-116 rapidly inhibits proliferation in the Hi-MYC model with a 50% decrease in Ki67 observed 12 hours after oral administration. Conversely, PMR-116 showed minimal anti-tumour efficacy in the PTEN-null model of PCa suggesting that elevated MYC signalling may be required for optimal response.
To further validate our promising GEMM results in more clinically relevant human-derived models, we used patient-derived xenografts lines we established from multidrug-resistant, metastatic PCa (Lawrence et al, European Urology, 2018). PMR-116 treatment decreased tumour volume in all PDX tested including complete response in a line in which tumour volume decreased by ~90% compared to baseline.
We believe this new RNA Pol I inhibitor shows promising results in a wide range of preclinical models and may exert higher efficacy in tumours expressing high levels of MYC. PMR-116 is currently in Phase I dose escalation trial in patient with solid tumours (ACTRN12620001146987).
Citation Format: Alisee Huglo, Richard Rebello, Mitchell Lawrence, Gail Risbridger, Denis Drygin, Mustapha Haddach, Katherine Hannan, Ross Hannan, Luc Furic. PMR-116, a novel inhibitor of ribosome biogenesis with antitumor activity in preclinical models of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2155.
Abstract 2176: NADPH production and redox homeostasis regulate acinar to ductal metaplasia
Authors: Radyk Megan D. , Nelson Barbara S. , Halbrook Christopher J. , Shan Mengrou , Alektiar Jonathan , Crawford Howard C. , Shah Yatrik M. , Lyssiotis Costas A. 
Published: June 2022

Abstract
Activating mutations in KRAS reprogram cellular metabolism to support continuous growth, proliferation, and survival in pancreatic cancer. However, there is little information on how KRAS-dependent alterations in metabolism change precancerous states and cancer initiation. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM), a reversible cell state that persists and progresses to neoplasia and cancer with oncogenic KRAS. During ADM, acinar cells transdifferentiate to duct-like cells, a process we hypothesized was mediated by metabolic rewiring. We performed transcriptomic analysis on acinar cells undergoing ADM and found metabolic programs are globally enhanced. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. A detailed analysis of our data revealed that the transcripts for NADPH-producing enzymes, Glucose-6-phosphate dehydrogenase (G6pd) and Malic enzyme 1 (Me1), were significant enriched during ADM. Following these results, we obtained G6pd-mutant mice and generated Me1flox/flox mice and bred them into the KC (KrasLSL-G12D/+;Ptf1aCre/+) line, resulting in KCG (KrasLSL-G12D/+;Ptf1aCre/+;G6pdmut/mut) and KCM (KrasLSL-G12D/+;Ptf1aCre/+;Me1flox/flox) mice. Interestingly, KCG and KCM mice develop ADM and neoplasia faster than their KC counterparts. We also observe that acinar cells and ADM in KCG cells have higher levels of lipid peroxidation and reactive oxygen species (ROS) both in vivo and using primary ex vivo acinar cell cultures. Thus, increased ROS levels may underlie ADM acceleration in this system. In primary acinar cell culture, we can rescue the accelerated ADM phenotype in KCG cells with the addition of antioxidants. Furthermore, we find that treatment of wild type acinar cells with buthionine sulphoximine (BSO) to deplete glutathione levels and increase ROS also accelerates ADM in culture. These results suggest that NADPH and glutathione pools are important for regulating redox levels during ADM, and that reducing these pools leads to accelerated tumorigenesis. Together, this work demonstrates new metabolic pathways driving pancreatic cancer initiation.
Citation Format: Megan D. Radyk, Barbara S. Nelson, Christopher J. Halbrook, Mengrou Shan, Jonathan Alektiar, Howard C. Crawford, Yatrik M. Shah, Costas A. Lyssiotis. NADPH production and redox homeostasis regulate acinar to ductal metaplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2176.
Abstract 2216: Impact of EXO1 (K589E) single nucleotide polymorphism on breast cancer risk in Bangladeshi women
Authors: Rahman Md. Mustafizur , Kabir Md. Mahmudul , Rahman Md. Abdur , Hossain Amir , Hossain Md. Golam 
Published: June 2022

Abstract
Background and aim: Exonuclease 1 (EXO1) is an essential member of the RAD2 nuclease family which is involved in mismatch repair system and contributes to the maintenance of genomic stability, modulation of DNA recombination and cell cycle arrest mediation. Potential polymorphism in EXO1 may have the ability to control cancer risks by influencing the repair activity. K589E (rs1047840) is a potentially functional polymorphism in EXO1 gene and we hypothesized that it might be associated with risk of breast cancer in Bangladesh.
Method: We designed a case-control study consisting of 184 subjects with breast cancer and 200 healthy controls to identify the effect of K589E polymorphism on breast cancer susceptibility and clinicopathological features in Bangladeshi women. Genotype determination was performed by PCR-RFLP method.
Results: After the adjustment of age and weight, a significant association was found between EXO1 K589E alleles and genotypes and risk of breast cancer. The frequencies of the three genotypes G/G, G/A, and A/A were 49, 42, and 9% in cases whereas 69, 27.5, and 3.5% in controls, respectively. The heterozygote G/A genotype and combined G/A+A/A genotypes showed 2.12-fold (OR=2.12, 95% CI=1.3733 - 3.2822 p=0.0007) and 2.27-fold (OR=2.27, 95% CI=1.5001 - 3.4493, p=0.0001) increased risk of breast cancer, respectively when compared with homozygous G/G genotypes. The variant A allele also was associated with increased risk of breast cancer (OR= 3.46, 95% CI=1.3720 - 8.7571, p=0.0086). Analysis of clinicopathological characteristics and genotype distribution also showed a significant correlation.
Conclusion: Our results revealed that EXO1 K589E polymorphism could be a potential predisposing risk factor in genetic susceptibility to breast cancer in Bangladesh.
Citation Format: Md. Mustafizur Rahman, Md. Mahmudul Kabir, Md. Abdur Rahman, Amir Hossain, Md. Golam Hossain. Impact of EXO1 (K589E) single nucleotide polymorphism on breast cancer risk in Bangladeshi women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2216.