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NSCLC treatment includes targeting of EGFR with tyrosine kinase inhibitors (TKIs) such as Erlotinib; however, resistance to TKIs is commonly acquired through T790M EGFR mutations or overexpression of vascular endothelial growth factor receptor-2 (VEGFR-2). We investigated the mechanisms of EGFR-TKI resistance in NSCLC cell lines with EGFR mutations or acquired resistance to Erlotinib. These studies showed upregulated gene and protein expression of VEGF, VEGFR-2, and a VEGF co-receptor neuropilin-1 (NP-1) in Erlotinib-resistant (1.4–5.3-fold) and EGFR double-mutant (L858R and T790M; 4.1–8.3-fold) NSCLC cells compared to parental and EGFR single-mutant (L858R) NSCLC cell lines, respectively. Immunofluorescence and FACS analysis revealed increased expression of VEGFR-2 and NP-1 in EGFR-TKI-resistant cell lines compared to TKI-sensitive cell lines. Cell proliferation assays showed that treatment with a VEGFR-2 inhibitor combined with Erlotinib lowered cell survival in EGFR double-mutant NSCLC cells to 9% compared to 72% after treatment with Erlotinib alone. Furthermore, Kaplan–Meier analysis revealed shorter median survival in late-stage NSCLC patients with high vs. low VEGFR-2 expression (14 mos vs. 21 mos). The results indicate that VEGFR-2 may play a key role in EGFR-TKI resistance and that combined treatment of Erlotinib with a VEGFR-2 inhibitor may serve as an effective therapy in NSCLC patients with EGFR mutations.

Background: Lung cancer is the leading cause of cancer-related deaths in the United States. In 2019, 23.5% of deaths from cancer in the United States were attributed to lung cancer, a greater proportion than those from breast, prostate, pancreatic, and ovarian cancers combined. Lung cancer's high mortality rate is largely due to the fact that approximately 75% of new cases are diagnosed in late stages. On a local level, Winnebago County has 17% higher incidence and mortality rates due to lung cancer than the corresponding national rates. Low-dose computed tomography (LDCT) is a valuable lung screening technique that utilizes 90% less ionizing radiation than a conventional chest CT scan. Hypothesis/Aims: Increased awareness of LDCT in clinical and community settings will lead to increased detection of lung cancer in early stages and decreased mortality. Study Design: We spread information on the new U.S. Preventive Services Task Force guidelines to both smokers and physicians in Winnebago County. We evaluated the number of LDCT screenings in Winnebago County between June 2015-March 2019, and recorded the number and stage classifications of lung cancer cases detected after these screenings. We also surveyed physicians and smokers on their likelihood of recommending LDCT to others after our seminars. Lastly, we created a Facebook page (Northern Illinois Lung Cancer Screening Project) to continue promoting LDCT screening in a socially distanced manner. Results: 15 seminars and 37 public awareness booths targeting an estimated 300 physicians and 1,450 smokers were conducted to increase knowledge of LDCT. 2,076 patients underwent LDCT screening at local hospitals. 28 patients were diagnosed with lung cancer, with 17 cases being early stage. 1,000 additional individuals were found to have small lung nodules. According to our surveys, 100% of attendees felt motivated to tell others about LDCT screening after attending our seminars. These studies are also being extended to Boone, Ogle, and Stephenson Counties, which have high incidence of mortality rates attributed to lung cancer. In an alternative effort to promote lung cancer screening in Northern Illinois, we created a Facebook page where we publish posts weekly and have reached over 1109 people and garnered 142 engagements from users. Conclusions: 17 local community members were diagnosed with early stage lung cancer, thus improving their prognosis and increasing therapy options. These community-based studies are being expanded to surrounding areas to expand the reach and effectiveness of our studies. Citation Format: Monica Saravana Vela, Joseph Berei, Katrina Dovalovsky, Shylendra Sreenivasappa, Joseph Ross, Luigi Moruzzi, Sandra Martell, William Schulz, Neelu Puri. Promotion of low-dose computed tomography for early-stage lung cancer detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2607.

Telomeres function as protective caps at the terminal portion of chromosomes, containing non-coding nucleotide sequence repeats. As part of their protective function, telomeres preserve genomic integrity and minimize chromosomal exposure, thus limiting DNA damage responses. With continued mitotic divisions in normal cells, telomeres progressively shorten until they reach a threshold at a point where they activate senescence or cell death pathways. However, the presence of the enzyme telomerase can provide functional immortality to the cells that have reached or progressed past senescence. In senescent cells that amass several oncogenic mutations, cancer formation can occur due to genomic instability and the induction of telomerase activity. Telomerase has been found to be expressed in over 85% of human tumors and is labeled as a near-universal marker for cancer. Due to this feature being present in a majority of tumors but absent in most somatic cells, telomerase and telomeres have become promising targets for the development of new and effective anticancer therapeutics. In this review, we evaluate novel anticancer targets in development which aim to alter telomerase or telomere function. Additionally, we analyze the progress that has been made, including preclinical studies and clinical trials, with therapeutics directed at telomere-related targets. Furthermore, we review the potential telomere-related therapeutics that are used in combination therapy with more traditional cancer treatments. Throughout the review, topics related to medicinal chemistry are discussed, including drug bioavailability and delivery, chemical structure-activity relationships of select therapies, and the development of a unique telomere assay to analyze compounds affecting telomere elongation.

Telomerase provides cancer cells with replicative immortality, and its overexpression serves as a near-universal marker of cancer. Anti-cancer therapeutics targeting telomerase have garnered interest as possible alternatives to chemotherapy and radiotherapy. Oligonucleotide-based therapies that inhibit telomerase through direct or indirect modulation of its subunits, human telomerase reverse transcriptase (hTERT) and human telomerase RNA gene (hTERC), are a unique and diverse subclass of telomerase inhibitors which hold clinical promise. MicroRNAs that play a role in the upregulation or downregulation of hTERT and respective progression or attenuation of cancer development have been effectively targeted to reduce telomerase activity in various cancer types. Tumor suppressor miRNAs, such as miRNA-512-5p, miRNA-138, and miRNA-128, and oncogenic miRNAs, such as miRNA-19b, miRNA-346, and miRNA-21, have displayed preclinical promise as potential hTERT-based therapeutic targets. Antisense oligonucleotides like GRN163L and T-oligos have also been shown to uniquely target the telomerase subunits and have become popular in the design of novel cancer therapies. Finally, studies suggest that G-quadruplex stabilizers, such as Telomestatin, preserve telomeric oligonucleotide architecture, thus inhibiting hTERC binding to the telomere. This review aims to provide an adept understanding of the conceptual foundation and current state of therapeutics utilizing oligonucleotides to target the telomerase subunits, including the advantages and drawbacks of each of these approaches.

In lung cancer, 81% of patients detected are late-stage, since early-stage patients are generally asymptomatic. Winnebago County has a 14% higher mortality rate for lung cancer when compared to the national rate; hence, to improve early detection of lung cancer in the Winnebago County, we implemented low-dose computed tomography (LDCT) screening. Currently, LDCT is used to detect lung cancer at early-stages, and the CDC has proposed new guidelines for early screening of lung cancer in individuals between 55-77 years of age with a 30 pack/year smoking history. Using circulating DNA from lung cancer patients and examining changes in methylation patterns in genes that are expressed in lung cancer patients can be used for early detection. Epidermal growth factor receptor (EGFR) is shown to be expressed in lung cancer patients’ serum in all stages; hence, it can be used as a potential biomarker for early detection. To improve early detection of lung cancer in the Winnebago County, we educated physicians/smokers about LDCT screenings to promote early detection of lung cancer. We evaluated the number of LDCTs performed and recorded the number of lung cancer cases detected in the Winnebago County between June 2015 to October 2017. To explore EGFR as a promising biomarker, plasma was separated from whole blood and collected. Circulating DNA was extracted with the MagMax cell-free circulating kit and bisulfite converted. Identification of percent methylation patterns in the EGFR promoter region in CpG islands was obtained after next generation sequencing (NGS) followed by bioinformatics analysis. In our study, 1,116 LDCT screenings occurred in the Winnebago County. Lung cancer was diagnosed in 19 patients, out of which 11 patients (57.8%) were early-stage patients. We detected 45.4% of patients screened that were present with nodules compared to 24.2% of patients in the National Lung Cancer Screening Trial. We observed that 1.70% of patients referred for LDCT screening were diagnosed with lung cancer, compared to 0.87% of patients in the National Lung Cancer Screening Trial. This may be due to the higher incidence of smoking in Winnebago County (18%) compared to the nation (15.5%). Our screening study had 96.3% false positives, which is comparable (96.4%) to the results obtained in the National Lung Cancer Screening Trial. Using NGS, methylation in the promoter region of EGFR was studied using degenerate EGFR primers. In the promoter region of EGFR, our analysis showed that there are regions of hypermethylation (68-86%) in three CpG islands in sequences at the beginning of the promoter (8-241 bases). However, there was hypomethylation (6-21%) at four CpG island further downstream (375-689 bases from the beginning of the promoter). Currently we are studying the methylation patterns in normal subjects to determine whether these regions which could be used as predictive biomarkers for early detection. Citation Format: Adijan Kuckovic, Joseph Berei, Shylendra Sreenivasappa, Joseph Ross, Sandra Martell, Connie Vitali, William Schulz, Neelu Puri. Lung cancer screening initiative and identification of novel blood biomarkers for early detection of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3329.