Lu Yang

Background Background parenchymal enhancement (BPE) at dynamic contrast-enhanced (DCE) MRI of cancer-free breasts increases the risk of developing breast cancer; implications of quantitative BPE in ipsilateral breasts with breast cancer are largely unexplored. Purpose To determine whether quantitative BPE measurements in one or both breasts could be used to predict recurrence risk in women with breast cancer, using the Oncotype DX recurrence score as the reference standard. Materials and Methods This HIPAA-compliant retrospective single-institution study included women diagnosed with breast cancer between January 2007 and January 2012 (development set) and between January 2012 and January 2017 (internal test set). Quantitative BPE was automatically computed using an in-house-developed computer algorithm in both breasts. Univariable logistic regression was used to examine the association of BPE with Oncotype DX recurrence score binarized into high-risk (recurrence score >25) and low- or intermediate-risk (recurrence score ≤25) categories. Models including BPE measures were assessed for their ability to distinguish patients with high risk versus those with low or intermediate risk and the actual recurrence outcome. Results The development set included 127 women (mean age, 58 years ± 10.2 [SD]; 33 with high risk and 94 with low or intermediate risk) with an actual local or distant recurrence rate of 15.7% (20 of 127) at a minimum 10 years of follow-up. The test set included 60 women (mean age, 57.8 years ± 11.6; 16 with high risk and 44 with low or intermediate risk). BPE measurements quantified in both breasts were associated with increased odds of a high-risk Oncotype DX recurrence score (odds ratio range, 1.27-1.66 [95% CI: 1.02, 2.56]; P < .001 to P = .04). Measures of BPE combined with tumor radiomics helped distinguish patients with a high-risk Oncotype DX recurrence score from those with a low- or intermediate-risk score, with an area under the receiver operating characteristic curve of 0.94 in the development set and 0.79 in the test set. For the combined models, the negative predictive values were 0.97 and 0.93 in predicting actual distant recurrence and local recurrence, respectively. Conclusion Ipsilateral and contralateral DCE MRI measures of BPE quantified in patients with breast cancer can help distinguish patients with high recurrence risk from those with low or intermediate recurrence risk, similar to Oncotype DX recurrence score. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Zhou and Rahbar in this issue.

The cell surface proteome provides a pivotal interphase that connects the intracellular signaling with external environments, which may harbor molecular targets for therapeutic development. To identify essential cell surface proteins in cancers, we established a CRISPR library that contains 2,910 sgRNAs targeting 582 genes encoding cell surface receptors (to cytokines, extracellular matrices [ECM], etc.), molecular channels, and signaling components. We then screened this library in 3 solid cancer (MDA-MB-231, SW620, PANC1) and 3 liquid cancer (MV4-11, HUT78, CCRF-CEM) cell models expressing the Cas9 endonuclease, and observed an essential role of ITGAV (Integrin Alpha V) specifically in the solid cancer. As integrins require the dimerization between an alpha and beta subunit to function as cell surface ECM receptors, we further developed a focused CRISPR library with 650 sgRNAs targeting all 26 integrin alpha and beta subunits. This validation screen revealed a strong correlation between ITGAV and ITGB5 (Integrin Beta 5) in solid tumors. CRISPR targeting either ITGAV or ITGB5 led to attenuated cell proliferation with increased cell cycle stalling and apoptosis. Knockout of ITGAV-ITGB5 also suppressed the capacity of tumor cells to migrate and invade through the ECM, highlighting the therapeutic benefit via blocking the ITGAV-ITGB5 heterodimer. To identify novel compounds that can disrupt ITGAV-ITGB5 dimerization, we first modeled a 3D crystal structure of ITGAV (PDB ID: 3IJE) using AutoSite (Scripps) to reveal the protein surface pockets amenable to the small molecular binding. This analysis revealed an AVB pocket at the N-terminal extracellular domain of ITGAV, which is in close contact with the beta subunit. CRISPR targeting this AVB pocket abolished the ITGAV-ITGB5 heterodimers (detected by an AV-B5-complex antibody) and induced rapid cell death, rationalizing this pocket for further therapeutic development. Based on these observations, we computationally docked >100,000 compounds from the NCI DTP Open Chemicals Repository using AutoDock Vina (Scripps), subsequently obtaining the top 500 binder compounds for in-lab validation, and identified a lead AVB pocket inhibitor “Cpd_2” (C₃₂H₄₀N₄). Treatment of Cpd_2 killed tumor cells and diminished the AV-B5-complex antibody stain. Furthermore, we confirmed the capacity of Cpd_2 to dissociate ITGAV and ITGB5 on the cell surface by a NanoBRET energy transfer system. Of note, while the traditional ITGAV inhibitor cilengitide (an RGD peptide mimic) blocked the ECM interaction and detached the cells from TC dishes, they failed to dissociate the ITGAV-ITGB5 heterodimer nor induce rapid cell death. In summary, our study highlights a novel strategy of targeting the ITGAV-ITGB5 heterodimer stability by the small molecular inhibitor Cpd_2 for future anti-tumor treatment. Citation Format: Nicole Mattson, Kazuya Miyashita, Anthony Chan, Lu Yang, Sheela Pangeni Pokharel, Wei Lu, Mingli Li, Qiao Liu, Xiaobao Xu, Mingye Feng, Chun-Wei Chen. Targeting integrin alpha V beta 5 heterodimer stability using a novel small molecular inhibitor for tumor suppression [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 2920.