United States

Background: 4-1BBL is a co-stimulatory molecule that is important for T-cell expansion and
induction of robust CD8+ T-effector and memory responses, critical for tumor rejection. The natural 4-1BBL is a trimeric transmembrane protein that has no activity in soluble form. To overcome this limitation, a unique soluble form of 4-1BBL was developed by linking core streptavidin (SA) to the extracellular domain of murine 4-1BBL (SA-4-1BBL). This chimeric protein forms oligomers that have pleiotropic effects on cells of innate, adaptive, and regulatory immunity. However, production and purification of SA-4-1BBL is cost- and time-intensive. Therefore, development of an expression platform that is more efficient, translational, and augments anti-tumor efficacy of SA-4-1BBL will have a significant impact for clinical development of this immune adjuvant. Thus, we developed a novel oncolytic adenoviral system to deliver SA-4-1BBL to solid tumors.
Methods: The AdenoQuick system was used to construct OAds expressing SA-4-1BBL or SA (control). Transgene expression was confirmed by western blot and SA-4-1BBL biological function was evaluated by splenocyte proliferation assay in vitro. The OAdSA-4-1BBL and
Ó 2022 American Medical Association. All rights reserved.
OAdSA-mediated cancer killing effect was evaluated by crystal violet staining, the activation of autophagy-mediated immunogenic cell death was assessed by detection of autophagy markers LC3-I, LC3-II and p62. The damage-associated molecular patterns molecules adenosine triphosphate, high-mobility group box 1, and calreticulin were evaluated by luminescence, ELISA, and flow cytometry, respectively. Tumor expression of SA, SA-4-1BBL, and Hexon was evaluated by immunohistochemistry. The OAdSA-4-1BBL therapeutic efficacy was evaluated in C57BL/6 mice-bearing subcutaneous TC-1 lung tumor.
Results: We successfully constructed OAds expressing SA or SA-4-1BBL. We demonstrated that SA-4-1BBL can produce biologically active oligomers, selectively induces autophagy- mediated immunogenic cell death in murine and human lung cancer cell lines with little cytotoxicity to normal cell lines. The transgene expressions within the subcutaneous tumor were confirmed and OAdSA-4-1BBL shows greater anti-tumor efficacy than control viruses in a TC-1 tumor mouse model.
Conclusion: Overall, our data suggests that OAd expressing the immune checkpoint stimulator SA-4-1BBL may represent alternative therapeutic strategy against lung cancer, which could be used alone or in combination with immune checkpoint inhibitors, or other approaches aimed at enhancing the anti-tumor immune response.

AMA Research Challenge 2022

Development and characterization of an oncolytic adenovirus armed with the immune checkpoint stimulator SA-4-1BBL

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Effect of Hesperetin against DMH induced toxicity in the colon of Wistar rats

Background
Glioblastoma (GBM) represents the most common primary malignant brain tumor in adults, with a median survival rate of less than two years. GBM presents with therapeutic resistance and high rates of recurrence, largely attributed to the presence of glioblastoma stem cells (GSCs). GSCs are frequently located in specific niches, including a hypoxic niche and a normoxic, perivascular niche. Targeting GSCs is a potential therapeutic avenue for treating GBM, but the details of GSC function in hypoxic conditions remains poorly understood. Further, most gene expression findings are limited to epigenetic or transcriptional regulation assays, overlooking the importance of the translatome. This study expands on conclusions made using steady-state mRNA levels by including ribosome profiling to evaluate translational regulation mechanisms. 

Methods
We selected two patient-derived GSC lines (GSC 215, GSC 316) and cultured them in both hypoxic (5% O2) and normoxic (21% O2) conditions. RNA-seq libraries were prepared in parallel with RIBO-seq libraries for the lines in both conditions, with biological replicates for each treatment group, after which Illumina sequencing was performed. Raw sequencing reads were assessed for quality. Single-end reads were aligned and counted using command line versions of STAR, BEDTools, and SAMTools. Differential changes in ribosome-protected fragments (∆RPF) and changes in transcript levels (∆RNA) were calculated using DESeq2. GO term analyses for transcripts was performed with Reactome using a hypergeometric statistical test and BH FDR correction.

Results
Comparing ∆RNA and ∆RPF levels between hypoxic and normoxic GSCs reveals 9 functional clusters of genes. These categories indicate genes which are post-transcriptionally controlled in 3 manners: translationally suppressed (28.19%), translationally upregulated (32.87%), or concurrently translated (38.93%). Altogether, more than 60% of mRNA show marked regulation on the translational level.

Significant enrichment of genes in the NOTCH signaling pathway (p = 1.09e-02), WNT signaling pathway (p = 1.37e-04), and RHO GTPase cycle (p = 2.37e-07) are present among the transcripts that experience translational upregulation in hypoxic conditions.

Conclusion
This study may lead to the identification of potential therapeutic targets as evidenced by their function as regulatory hubs in cellular networks responsible for hypoxic adaptation. These observations are largely undetected by RNA-seq measurements.


Evaluating the Role of Translation Regulation in Glioblastoma Stem Cells for Hypoxic Adaptation

First-in-class Heterobifunctional Proteomimetic Polymer Capable of Direct Inhibition and Targeted Degradation of Myc

In silico modeling of LAT1 efflux agonists for the treatment of pancreatic cancer

Neuroblastoma is the most common extracranial solid tumor in children. It accounts for more than 7% of malignancies in patients less than fifteen years of age and makes up 15% of oncology deaths. Neuroblastoma is a cancer derived from primordial neural crest cells under conditions of inappropriate migration, maturation, and or differentiation. These extracranial tumors are formed in the adrenal medulla, sympathetic ganglia, and abdomen. Current treatments for neuroblastoma include surgery, chemotherapy, radiotherapy, and biotherapy. Interestingly, neuroblastoma tumors are heterogenous with some children having low-risk tumors that regress entirely while others have high-risk tumors with widespread metastasis and poor outcomes. The expression of MYCN, a gene in a family of oncogenic drivers, in neuroblastoma tumors has been associated with high-risk neuroblastoma and worse outcomes. Children with high-risk neuroblastoma account for approximately half of all patients diagnosed with neuroblastoma. Despite current interventions and aggressive treatment, children with high-risk neuroblastoma have a long-term survival rate of less than 50%. Currently, there are not many targeted therapies for high-risk neuroblastoma as there is little know about the mechanism driving this cancer. By identifying the mechanism driving tumor progression, a treatment to specifically target the different steps of this cancer can be created. Signaling through neuronal nicotinic acetylcholine receptors (nAChRs) is involved in many neuronal processes of neural tissue, including the proliferation of neural crest cells. These receptors are a diverse group of ligand-gated pentametric channels can exist as homopentamers or heteropentamers of α or β subunits. The only mammalian homopentamer is the α7 receptor that when activated is suggested to promote neural cell survival. Furthermore, expression of nAChR has been shown to be regulated by MYCN. Our lab is interested to see if MYCN-expressing neuroblastoma tumors upregulate the expression of nAChRs leading to an overall drive in tumor progression. Therefore, targeting this interaction between nAChRs and MYCN can become a potential therapy of high-risk neuroblastoma. 


N-MYC Transcription Factor Increases the Expression of Alpha-7 Nicotinic Acetylcholine Receptor Promoting Cell Viability in Neuroblastoma Cell Line

Background and Premise: Triple-negative breast cancer (TNBC) is an aggressive, metastatic disease with high mortality. The standard-of-care neoadjuvant chemotherapy (NACT) shows an initial response but followed by a drug resistance, increase in tumor relapse and distant metastases. Immunotherapy against programmed death ligand-1 (PD-L1) has shown efficacy in treating a subset of TNBC patients. However, it shows resistance in other patients due to new immune checkpoints such as VISTA, TIGIT, and LAG3. 

eIF4A1 is a mRNA helicase known to translate many oncogenic mRNAs including survivin, c-MYC, ROCK1, STAT1, ARF6 etc., We previously established that eIF4A1 is a vulnerable target in drug-resistant TNBC. Interestingly, we observed a reduction in levels of PD-L1 when eIF4A1 is targeted. Many downstream effectors of eIF4A1 such as c-MYC, STAT1 and ARF6 are indeed upstream regulators of PD-L1. This premise formed the basis to co-target eIF4A1 and PD-L1. Before that, we need to establish the clinical relevance of these targets in human TNBC biospecimens. This will ascertain the differential operation of the eIF4A1-PD-L1 axis in therapy-naïve and drug-resistant primary and mTNBC.

Approach: Human biospecimens obtained from CHTN NIH repositories (more than 100 TNBC primary tumor and metastatic biospecimens) will be analyzed for role of eIF4A1 in translation of oncogenic mRNAs that contribute to PD-L1 and other emerging immune checkpoint markers such as VISTA, TIGIT, and LAG3 via immunohistochemistry (after deglycosylation for effective detection of PD-L1) and also by immunoblotting. 

Results: The levels of total eIF4A1 from 16 matched, therapy naive TNBC tissue were compared to adjacent normal breast tissue from the same patient via immunoblotting. Total eIF4A1 levels were found to be significantly elevated in TNBC compared to adjacent normal tissue. The downstream effectors of eIF4A1 such as STAT1 and ARF6 were also significantly elevated indicating a robust helicase activity of eIF4A1. Importantly, PD-L1 levels was found to be elevated. Additionally, the total eIF4A1 level were elevated in drug-resistant tumors than normal breast tissue samples as assesses by immunohistochemistry. 

Conclusion: The eIF4A1-STAT1-PD-L1 axis is highly active in TNBC especially in drug-resistant situations. Currently, we are evaluating other immune checkpoints such as VISTA, TIGIT, and LAG3. 


Operation of eIF4A1-PD-L1 axis in therapy-naïve and drug-resistant TNBC

Background
Given basic advances in cancer immunotherapy, further understanding of potential antigenic targets will improve treatment protocols. Cancer testes antigens (CTAs) are relatively novel proteins to consider in the overlap of the breast cancer and immunotherapy setting. CTAs are normally expressed in benign testis and placenta; and show aberrant expression in many malignancies, including breast cancer. This work indicated that the CTA, ARMC3 (Armadillo repeat-containing protein 3) is commonly expressed in breast cancer, and when evaluated for its chemical relationship to breast cancer resident T-cell receptor (TCR) chemical features, there was an indication of T-cell response to ARMC3. This result was substantially informed by survival data and granzyme expression.
Methods
The software used for the recovery of TCR recombination reads is available at https://github.com/bchobrut-USF/blanck_group. TCR alpha and TCR beta recombination data were extracted from the National Institutes of Health (NIH) genomics datasets. Chemical complementarity scores (CSs) were determined using the software available at https://github.com/bchobrut/brca_swcs. Linkage of chemical CSs to survival rates, and to RNAseq values (for assessing gene expression), was done with a web tool designed for these purposes termed, adaptivematch.com. Kaplan-Meier analysis conducted to compare survival probability for the upper and lower 50th percentiles of CSs. Multivariate analysis of age, race, menopause, cancer stage was performed for ARMC3-based CSs. 
Results 
Among a set of approximately 280 CTAs, ARMC3 expression stood out as representing a strong distinction for survival rates for both OS and DFS (OS p=0.0147, DFS p=0.0105). We next considered the possibility that a TCR CDR3-ARMC3 interaction would be consistent with the expression of immune biomarkers. Results indicated higher RNA expression of certain immune markers with increasing CS values. There was a survival distinction for the upper and lower 50th percentiles of CSs, with the upper 50th percentile representing a greater disease-free survival probability. Only the tumor stage and the ARMC3 based CS represented independent factors associated with survival distinctions.
Conclusion
For the ARMC3 expression; the higher the expression level, the better the survival probability. CS assessments of TCR CDR3-CTA pairs may indicate targetable antigens and may be useful for risk stratification and guiding therapy in breast cancer.


T-cell Receptor (TCR) Chemistry And Survival Data Support The Consideration Of ARMC3 As A Breast Cancer Antigen

Metastatic triple-negative breast cancer (mTNBC) has poor prognosis. Neoadjuvant chemotherapy (NACT) such as taxanes showed an initial treatment response but followed by drug resistance, tumor relapse, and metastases. The chemoresistance is even observed in targeted PARP1 therapy. Hence, there is an unmet need for. developing effective combination therapies against mTNBC. eIF4A1 is an mRNA helicase involved in translation of a subset of oncogenic mRNAs including c-MYC, cyclins D1 and D3, STAT1 etc., Previously, we discovered that eIF4A1 may regulate cancer stemness and drug resistance in TNBC. Furthermore, we found that protein levels of eIF4A1 and STAT1 were upregulated in NACT-resistant than therapy-naïve human TNBC biospecimens. STAT1 is an upstream regulator of PD-L1. Additionally, when eIF4A1 is targeted in paclitaxel-resistant human TNBC cells, PD-L1 was downregulated. Based on this premise, we targeted eIF4A1 with a small molecule inhibitor Rocaglamide A (RocA) and anti-PD-L1 immunotherapy as an effective therapeutic strategy in a murine TNBC model.

Targeting of eIF4A1 along with anti-PD-L1 therapy limits lung metastases efficaciously in triple-negative breast cancer

Background
TCEP is an organophosphorus flame-retardant (OPFR) widely used in polyurethane foams and household products. From these materials, TCEP emits into the surrounding environment, which humans encounter through inhalation and dermal absorption. Previous studies have shown OPFRs to have endocrine disrupting actions, and thus, influence diseases such as cancer. Breast cancer is the second most common cancer among women in the United States, and because of this prevalence, it is imperative to investigate possible carcinogens. Due to the endocrine disrupting nature of OPFRs, we are investigating the effects of TCEP on hormone-dependent breast cancer cell lines MCF-7 and T-47D.

Methods
Our study examines the effects of TCEP, alone and in combination with hormones and anti- hormones, on ERα and BRCA-1 expression in MCF-7 and T-47D breast cancer cell lines by utilizing western blot analyses, cellular viability assays, confocal microscopy, and RT-qPCR analyses. In order to deplete any endogenous steroids or effectors, breast cancer cells were cultured in a medium containing 5% charcoal-stripped fetal bovine serum for six days.

Results
Western blot analysis revealed alterations in ERα and BRCA-1 expression after 24 hours of treatment with varying TCEP concentrations (1μM-2mM). Analysis revealed a concentration- dependent increase in BRCA-1 expression in both cell lines, and a concentration-dependent decrease in ERα expression in the T-47D cell line. During hormonal studies, cells were treated with an optimum concentration of TCEP along with combinations of hormones and anti- hormones. After 24-hour treatment with a combination of E2 + TCEP, a significant decrease in ERα expression was observed in both cell lines. A significant increase of BRCA-1 expression occurred after 24-hour treatment of TCEP + E2 in both cell lines. These effects were sensitive to the presence of antiestrogens. Cellular viability assays revealed a significant increase in cellular viability in both cell lines when treated with a combination of E2 + TCEP.

Conclusion
Our results suggest that TECP acts as an endocrine disrupting compound on the steroid receptors and tumor suppressor genes in breast cancer cells. Further studies are warranted to determine the exact mechanism of action and influence of TCEP on breast cancer progression.

The Effects of Tris(2-Chloroethyl) phosphate (TCEP) on the Expression of Estrogen Receptor α (ERα) and Tumor Suppressor BRCA-1 in MCF-7 and T-47D Breast Cancer Cell Lines

Abstract Title: A national inpatient study: Risk factor analysis of venous thromboembolism in cancer.
Author name(s) and title(s): Satya Rijal MD, Gagan Kaur MD, Chia Chi Loh MD, Sowmya Sagireddy MD
Background: Venous thromboembolism is a condition that is associated with significant morbidity and mortality in cancer and its prevalence has increased proportionally in cancer inpatients. There has been a limited study in the past to evaluate the all-cause mortality and risk factor analysis of VTE in cancer. The goal of our study is to evaluate the mortality risk of cancer patients in VTE and establish the relationship between demographic characteristics and medical comorbidities in cancer inpatients with the risk of venous thromboembolism.
Methods: We conducted a retrospective cohort study using the nationwide inpatient sample (NIS, 2012-2014) total of 339,395 patients which included hospitalized patients with a primary diagnosis of cancer and divided into groups with VTE (N = 7,700) and without VTE (N = 331,695). We applied the binomial logistic regression model in our study to measure the odds ratio (OR) of demographic characteristics, comorbidities, and in-patient mortality rate associated with cancer patients with VTE.
Results: The highest majority of VTE in cancer inpatients were middle-aged adults of 36-50 years (83.1%), males (50%), blacks (19.3%), and followed by Hispanics (17.2%). While comparing the medical comorbidities, VTE risk was prevalent in cancer inpatients with CHF (OR 2.68, 95%CI: 2.30-3.12), followed by hypertension (OR 1.23, 95% CI: 1.16-1.29), diabetes (OR 1.16, 95%CI: 1.07-1.26), and chronic pulmonary disease (OR 1.13, 95%CI: 1.05-1.22). The prevalence of all-cause mortality was significantly higher with VTE (12%) carrying an increased risk of in-hospital mortality rate approximately four-fold (OR 3.87, 95% CI: 3.58-4.18).
Conclusion: The substantial difference in cause and effect of the current thromboprophylaxis use made it important to study the prevalence and in-hospital mortality risk factors of VTE in cancer which allows us for improving medical management by identifying patients at risk and formulating treatment and disease prevention strategies in healthcare settings. Our study could not include some comorbidities and lacks detailed patient-oriented clinical data that might affect the relationship between the risk of VTE in cancer, so we might require a large clinical trial including other comorbidities in the future to better explain the usefulness and outcomes related to risk factors of VTE in cancer inpatients.



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