Increasing amounts of genetic data have led to the development of polygenic risk scores (PRSs) for a variety of diseases. These scores, built from the summary statistics of genome-wide association studies (GWASs), are able to stratify individuals based on their genetic risk of developing various common diseases and could potentially be used to optimize the use of screening and preventative treatments and improve personalized care for patients. Many challenges are yet to be overcome, including PRS validation, healthcare professional and patient education, and healthcare systems integration. Ethical challenges are also present in how this information is used and the current lack of diverse populations with PRSs available. In this review, we discuss the topics above and cover the nature of PRSs, visualization schemes, and how PRSs can be improved. With these tools on the horizon for multiple diseases, scientists, clinicians, health systems, regulatory bodies, and the public should discuss the uses, benefits, and potential risks of PRSs.

Background: Despite considerable advances to improve colorectal cancer (CRC) survival over the last decade, therapeutic challenges remain due to the rapid metastatic dissemination of primary tumors. This study revealed the apoptotic and anti-growth mechanism of VTD, a previously used anti-hypertensive supplement, can elevate UBXN2A, a known tumor suppressor protein in CRC, and simultaneously enhance intrinsic and extrinsic apoptosis in metastatic cancer cells. Methods and Results: An AOM/DSS mouse model of CRC showed that UBXN2A haplosufficient (UBXN2A +/−) mice treated with VTD had less tumor burden than mice with the full UBXN2A gene treated with vehicle. We have previously shown that casein-coated mesoporous silica nanoparticles (MSNs) offer an effective local delivery of drugs at tumor sites. Our findings demonstrate that the high rate of extracellular release of matrix metalloproteinases (MMPs), particularly MMP-7, by metastatic colon cancer cells, triggers the release of VTD from casein-coated mesoporous MSNs. This shows the “Zip Code” mechanism for the local enrichment of VTD at the tumor sites. After in vitro drug release verification, two independent mouse experiments, a xenograft and a splenolepatic metastatic mouse model of CRC, were used to evaluate the therapeutic efficacy of VTD-loaded and casein-coated carboxylated mesoporous silica nanoparticles, MSN-COOH/VTD/CAS (VTD, 0.2 mg/kg). Animal experiments revealed that MSN-COOH/VTD/CAS (VTD, 0.2 mg/kg) slows down the progress of tumors. Mass spectrometry (MS) revealed improved pharmacokinetics (PK) profile as MSN-COOH/VTD/CAS had less VTD accumulation in non-cancerous organs compared to pure VTD. We further improved nanoparticle targeting and drug release by shifting to calcium-based particles (CBPs). The engineered CBPs demonstrated higher drug-releasing performance. Without the MMPs trigger, MSNs show slow and continuous “drug leak” over longer period of time whereas CCSMPs stops leakage within an hour. Additionally, CBPs showed higher sensitivity to MMP-7 than MMP-9, enhancing the targetability of CBPs for CRC metastatic tumors with excessive extracellular MMP-7. Conclusions: This study introduces a new platform utilizing nanoparticle-based site-specific delivery of a plant-based anti-metastatic molecule, veratridine, with enhanced safety and therapeutic efficacy for the treatment of metastatic CRC.

Breast cancer (BC) is a complex disease affecting one in eight women in the USA. Advances in population genomics have led to the development of polygenic risk scores (PRSs) with the potential to augment current risk models, but replication is often limited. We evaluated 2 robust PRSs with 313 and 3820 SNPs and the effects of multiple genotype imputation replications in BC cases and control populations. Biological samples from BC cases and cancer-free controls were drawn from three European ancestry cohorts. Genotyping on the Illumina Global Screening Array was followed by stringent quality control measures and 20 genotype imputation replications. A total of 468 unrelated cases and 4337 controls were scored, revealing significant differences in mean PRS percentiles between cases and controls (p < 0.001) for both SNP sets (313-SNP PRS: 52.81 and 48.07; 3820-SNP PRS: 55.45 and 49.81), with receiver operating characteristic curve analysis showing area under the curve values of 0.596 and 0.603 for the 313-SNP and 3820-SNP PRS, respectively. PRS fluctuations (from ~2–3% up to 9%) emerged across imputation iterations. Our study robustly reaffirms the predictive capacity of PRSs for BC by replicating their performance in an independent BC population and showcases the need to average imputed scores for reliable outcomes.

Despite considerable advances to improve colorectal cancer (CRC) survival over the last decade, therapeutic challenges remain due to the rapid metastatic dissemination of primary tumors. Nearly 50% of colorectal cancer (CRC) patients develop liver metastases. This shows the pressing need to develop more effective targeted therapies to decrease the high mortality rates associated with metastatic disease. This study revealed the apoptotic and anti-growth mechanism of veratridine (VTD), a previously used anti-hypertensive supplement. VTD can elevate UBXN2A, a known tumor suppressor protein in CRC, and simultaneously enhance intrinsic and extrinsic apoptosis in metastatic cancer cells. An AOM/DSS mouse model of CRC showed that UBXN2A haplosufficient (UBXN2A +/-) mice treated with VTD had less tumor burden than mice with the full UBXN2A gene treated with vehicle. Recently, we reported that the trypsin-triggered release of anti-cancer small molecules from casein-coated mesoporous silica nanoparticles (MSNs) offers an effective local delivery of drugs at tumor sites. Our findings demonstrate that the high rate of extracellular release of MMPs, particularly MMP-7 by metastatic colon cancer cells, triggers the release of VTD from casein-coated mesoporous MSNs. This shows the "Zip Code" mechanism for the local enrichment of VTD at the tumor sites. MMPs, particularly MMP-7, play a crucial role in CRC liver tumor invasion and formation of metastatic lesions due to their ability to degrade extracellular matrix proteins. Under physiological conditions in non-cancerous cells, the extracellular release of MMPs is limited to a low physiological range; therefore, VTD will not be released at normal non-cancer tissues. After in vitro drug release experiments, two independent mouse experiments, a xenograft and a spleno-hepatic metastatic mouse model of CRC, were used to evaluate the therapeutic efficacy of VTD-loaded and casein-coated carboxylated mesoporous silica nanoparticles, MSN-COOH/VTD/CAS (VTD, 0.2mg/kg). The number and size of developed tumor masses revealed that MSN-COOH/VTD/CAS (VTD, 0.2mg/kg) slows down the progress of tumors in both xenograft and CRC liver mouse models. Based on the in vivo results, we decided we could further improve nanoparticle targeting and drug release; hence, we refocused on calcium-based particles. Calcium carbonate microparticles (CCMPs) and calcium carbonate submicroparticles (CCSMPs) demonstrated higher drug-releasing performance compared to silica-based nanoparticles, MSNs. Without the MMPs trigger, MSNs show slow and continuous “drug leak” over longer period of time whereas CCSMPs stops leakage within an hour. Additionally, CCSMPs showed higher sensitivity to MMP-7 than MMP-9, enhancing the targetability of CCSMPs for CRC metastatic tumors with excessive extracellular MMP-7. The ability of MMP-7 and MMP-9 to release a drug from casein-coated calcium carbonate particles further expands the material platform for the development of targeted gated drug delivery and release using small anti-metastatic molecules. The target delivery strategy offers the dual benefit of enhancing anticancer effects while minimizing potential side effects on healthy cells, maximizing overall therapeutic efficacy.