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Daniel L Worthley

Publications and source records attributed to Daniel L Worthley.

8 recordsLinked to original sources
PubMed2026

Selective Macrocyclic WEE1 Kinase Inhibitors with Strong Efficacy against Patient-Derived Colorectal Cancer Organoids.

Macrocyclization can enhance the selectivity of acyclic compounds toward structurally similar biological targets such as kinases. WEE1 regulates cellular homeostasis and is a promising target in oncology. The clinical candidate AZD1775 (1) failed to progress past Phase II trials because of patient tolerability issues, likely due to off-target inhibition of polo-like kinase 1 (PLK1). Herein, a computer-aided drug design approach was conducted to develop a macrocycle based on the 1-WEE1 X-ray cocrystal structure. Significantly enhanced WEE1 inhibitory selectivity over PLK1 was determined for leading macrocycle 2, which also demonstrated broader kinome-wide selectivity. Patient-derived organoids from colorectal cancer (CRC) peritoneal and liver metastases, treated with 2, demonstrated comparably strong or enhanced anticancer efficacy compared to that of 1. Against patient-matched normal colon vs primary CRC organoids, 2 potently and selectively treated CRC, as well as enhanced DNA damage compared to 1. Finally, the X-ray cocrystal structure of 2 bound to WEE1 validated its computationally predicted bioactive binding mode.

Humans↗
PubMed2006

Many participants in fecal occult blood test population screening have a higher-than-average risk for colorectal cancer.

OBJECTIVES: Population-based colorectal cancer screening by fecal occult blood testing reduces cancer-specific mortality. Current guidelines recommend this strategy for average risk individuals. This study investigated the prevalence of higher-than-average risk characteristics, and rate of prior colonoscopy, in participants in fecal occult blood test screening programs. METHODS: Randomly selected individuals aged 50-74 years in urban Adelaide were offered free fecal occult blood test screening by mail, without prior knowledge of their medical status. Each invitation included a questionnaire to record the prevalence of higher-than-average risk characteristics related to symptoms, family history or comorbidity, as well as prior colonoscopy. The definition of average risk was taken from updated guidelines published by the US Multisociety Task Force on Colorectal Cancer. RESULTS: Of 2538 responses analyzed, 425 individuals had had a colonoscopy within the last 5 years, 106 fulfilled family history criteria for an initial screening colonoscopy, 209 had past polyps and 26 had had colorectal cancer. Eighty-three reported recent rectal bleeding. By current guidelines, 23% of the screened population did not warrant fecal occult blood test, because either prior colonoscopy rendered it unnecessary or particular patient characteristics made colonoscopy a more appropriate initial investigation. CONCLUSIONS: Fecal occult blood test screening programs capture a sizeable number of higher-than-average risk individuals that may warrant colonoscopic rather than fecal occult blood test screening. Other participants have had a recent colonoscopy and probably warrant a delay in screening. Mass population fecal occult blood test-based screening programs need to more effectively target those at average risk and should divert those of higher or lower risk to more individualized assessment.

Aged↗
PubMed2005

Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.

BACKGROUND & AIMS: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder caused by familial mutations in some of the genes responsible for DNA mismatch repair. Mutations in the MLH1, MSH2, and MSH6 genes have been documented in this disorder, but there have been limited and conflicting data about the role of another mismatch repair gene, PMS2. It has recently been suggested that mutations in the PMS2 gene do not cause an autosomal dominant disorder. In addition, mutations in each of these 4 mismatch repair genes have been shown to cause an autosomal recessive cancer syndrome in children that is distinct from hereditary nonpolyposis colorectal cancer. We reviewed a cohort of patients for evidence of an autosomal dominant disorder caused by a mutation in the PMS2 gene. METHODS: A cohort of tumor samples from patients with features suggestive of HNPCC was tested for microsatellite instability, the molecular hallmark of HNPCC, and exclusive loss of expression of the PMS2 gene in tumor tissue. RESULTS: A kindred was identified with autosomal dominant HNPCC due to a familial loss-of-function mutation in the PMS2 gene. This is the first description of such a kindred. CONCLUSION: Mutations in the PMS2 gene can, like mutations in other mismatch repair genes, cause both autosomal dominant HNPCC in adults and an autosomal recessive cancer syndrome in children.

Adenocarcinoma↗