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Published in Science Advances, the breakthrough sheds light on personalized cancer treatments
Scientists at Duke-NUS Medical School have made a significant breakthrough in understanding why certain pancreatic and colorectal cancers fail to respond to a promising new class of cancer drugs known as Wnt inhibitors. These inhibitors, designed to block the Wnt pathway responsible for driving tumor growth, hold immense potential for treating these cancers. However, the research, led by Dr. Zhong Zheng and Professor David Virshup, reveals that intrinsic resistance in some patients poses a challenge to the effectiveness of these drugs.
Gastrointestinal cancers, including colorectal and pancreatic cancers, often exhibit uncontrolled growth due to mutations in the Wnt pathway. Wnt inhibitors have emerged as a beacon of hope in cancer therapy, with Duke-NUS at the forefront of their development. However, Dr. Zhong’s study highlights a crucial obstacle: while some patients respond positively to Wnt inhibitors, others show resistance, necessitating a deeper understanding of the underlying mechanisms.
The researchers focused on cancers with hyperactive Wnt pathways, utilizing the Wnt-inhibiting drug ETC-159 to assess responsiveness. Through genetic analysis of tumor samples, they identified a second mutation in the FBXW7 gene, present in about 15 percent of colorectal cancers, as a key factor in conferring resistance to Wnt-blocking drugs. This mutation essentially alters the behavior of cancer cells, rendering them indifferent to the effects of Wnt inhibitors.
Dr. Zhong emphasizes the importance of this finding, stating that testing tumors for FBXW7 mutations could prevent ineffective treatment, serving both as a biomarker and a target for new therapies. This discovery not only enhances our understanding of drug resistance but also opens avenues for more tailored treatment strategies.
Senior author Prof. Virshup underscores the significance of predicting drug resistance in precision oncology, envisioning the targeting of alternative cancer pathways activated by FBXW7 mutations as a potential solution. The team’s findings not only shed light on resistance mechanisms but also offer new possibilities for overcoming them.
The study’s translational nature underscores Duke-NUS’ commitment to personalized cancer treatment. Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, emphasizes the importance of understanding cancer diversity to deliver effective, tailored therapies. With colorectal cancers being the second most common cancer in Singapore and pancreatic cancer ranking tenth among men, these findings hold immense promise for improving cancer treatment outcomes globally.
The research team’s next steps involve investigating the potential of an experimental drug, dinaciclib, alone and in combination with other agents, to treat Wnt inhibitor-resistant tumors. Ultimately, their goal is to develop more potent and personalized treatment strategies for patients with fully resistant tumors, bringing us one step closer to the vision of making every cancer a treatable disease.
In light of the World Health Organization’s estimation of over 1.9 million new cases of colorectal cancer diagnosed worldwide in 2020 alone, the significance of these findings cannot be overstated. As Duke-NUS continues its pioneering research, the prospect of personalized cancer therapies becomes increasingly tangible, offering hope to patients worldwide.
