Participants cited low patient demand and few physician referrals as barriers, but few centers reported needing additional staff or equipment. Those interviewed discussed the importance of a multidisciplinary team and overcoming barriers related to insurance reimbursement, costs, and physician knowledge to improve program implementation.
In our sample, we found that a majority of respondents were engaged in LDCT screening programs. Growth of such programs is expected in the coming years. Finalizing screening guidelines and insurance reimbursement will likely remove barriers that inhibit further growth of LDCT lung cancer screening programs.
e15093 Background: Phosphoinositide 3-kinase (PI3K) is an attractive anti-cancer drug target due to its promotion of cell growth and proliferation; however, available pan-PI3K inhibitors currently lack specificity, leading to excessive drug toxicity and adverse effects. Selectide-18 is a novel PI3K inhibitor that targets PI3K’s catalytic subunit p110β, resulting in reduced viability of cancer cells. The p110β subunit is the most prominent PI3K subunit in many chemoresistant tumors. Previous research has revealed a unique 18-residue long motif within the C2 domain of p110β. This motif is not found in other catalytic subunits (p110α, p110δ, or p110γ), making it a promising drug target. Selectide-18 is a memetic peptide drug modeled after this motif and has been shown to effectively inhibit p110β binding without affecting other isoforms, separating it from currently available pan-PI3K inhibitors. While Selectide-18 has been successful in inhibiting PI3K in previous studies, it has poor cell permeability due to its large size. Previous findings have revealed functional redundancies among Selectide-18’s residues. This study aims to remove these redundancies and determine the optimal formulation of Selectide-18 through in silico analysis. Methods: An in silico protocol was developed to determine the optimal formulation of Selectide-18. By utilizing the PEP-FOLD server, 455 peptide models were created using 91 unique fragments of the Selectide-18 amino acid sequence ranging in size from 6 to 17 residues. Physical conformation of each model was compared to wild-type Selectide-18 using root-mean-square deviation data collected using PyMOL and UCSF Chimera software. Computational docking through AutoDock Vina was performed to test the binding affinity of each model to the active site of regulatory subunit p85α. The distance between each drug and the active site was measured with UCSF Chimera’s distance function. Finally, ClusPro docking of drug-bound p85α/p110β was compared to wild-type p85α/p110β, as well as non-truncated Selectide-18-bound p85α/p110β. Statistical significance was determined using a Student's t-test. Results: Select truncated models demonstrated physical confirmation (RMSD = 0.024), binding affinity (-8.74 kcal/mol), and simulated inhibitory capabilities comparable to Selectide-18. A specific group of variants comprised of 9 amino acids (9 residue_6K-14Q) had the shortest formulation without significant declines in binding affinity. Conclusions: Selectide-18 is a selective PI3K inhibitor that can be optimized by removing functionally redundant amino acids. A 9-residue variant ranging from amino acids 6Lys to 14Gln showed the most promise and will be used in future studies to reformulate Selectide-18. Being half the size of Selectide-18, this optimized drug is anticipated to have improved cell permeability without sacrificing inhibitory function.
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