by University of Texas M. D. Anderson Cancer Center
The first-in-class YAP/TEAD inhibitor VT3989 was well tolerated with durable antitumor responses in patients with advanced malignant mesothelioma and other tumors with NF2 mutations, according to results of a Phase I trial led by researchers at The University of Texas MD Anderson Cancer Center. The first-in-human study was presented today at the American Association for Cancer Research (AACR) Annual Meeting 2023.
Seven of 69 patients had radiological partial responses that persisted up to at least 21 months, indicating tumor shrinkage, while 34 had stable disease. Patient benefit was observed in patients with both mesothelioma and other solid tumors, including those with and without NF2 mutations.
"This is the first clinical proof-of-concept for drugging the Hippo-YAP-TEAD pathway," said presenter and lead author Timothy A. Yap, M.D., Ph.D., associate professor of Investigational Cancer Therapeutics. "We've long known that YAP is a key oncogenic driver of cancer, and preclinical research suggested blocking YAP could shrink tumors. However, this is the first data demonstrating that targeting YAP can work in a clinical setting to actually benefit patients."
YAP (yes-associated protein) is a transcriptional co-activator that works with TEAD (transcriptional enhancer activator domain) as a part of the Hippo signaling pathway, which is important for normal cell growth and regulating the immune response. However, in several cancer types, YAP is either overexpressed or over-activated due to dysfunction in the pathway, fueling cancer cell growth. Therefore, YAP represents an attractive therapeutic target.
VT3989 works by inhibiting TEAD palmitoylation, which in turn blocks YAP function. NF2-mutant cancers were chosen for this trial due to their dependence on YAP activity for growth.
The Phase I dose escalation trial was designed to evaluate the safety, tolerability and recommended Phase II dose for VT3989. Today's presentation includes data on 69 enrolled patients, including 43 with advanced malignant mesothelioma and 26 with other solid tumors. Patients were heavily pre-treated and received a median of three prior lines of therapy. A total of 37 patients had NF2 mutations. Patients in the trial were 51% male and 49% female, 87% white, 10% Hispanic and 3% Black, with a median age of 63.5.
The drug was well tolerated, with no dose-limiting toxicities observed. The most common adverse events were albuminuria (a reversible increase in the protein albumin in the urine), swelling in the extremities, fatigue and nausea. Only seven grade 3 adverse events were possibly treatment-related, including albuminuria, swelling, fatigue, and increased liver enzymes alanine transaminase and aspartate aminotransferase, along with one possibly related grade 4 cardiomyopathy.
"These are early but very promising results showing that this previously 'undruggable' target and anti-cancer strategy can work in a clinical setting," Yap said. "We look forward to future results from this study in order to evaluate whether this approach may bring an urgently needed treatment option to these patients."
Ongoing dose optimization cohorts of the study are investigating different dosing and scheduling in two-stage designs.
More information: Abstract: www.abstractsonline.com/pp8/#! … 8/presentation/10247
Provided by University of Texas M. D. Anderson Cancer Center
by Daegu Gyeongbuk Institute of Science and Technology (DGIST)
The DGIST Core Protein Resources Center and Honam National Institute of Biological Resources announced that they have molecularly elucidated the mechanism by which veratramine, extracted from the wild island plant Veratrum japonicum, inhibits the proliferation of prostate cancer cells.
Prostate cancer ranks first in incidence among male cancers in Western countries including the United States, and it is also the fastest-growing male cancer in South Korea. In the early stages of onset, hormone suppression therapy can control proliferation; however, as the disease progresses, it becomes hormone-refractory, making treatment more difficult. Therefore, developing treatments using natural substances without side effects is considered an important area of research.
Veratramine extracted from Veratrum japonicum, a wild island plant, has been known to inhibit the proliferation of liver cancer and brain neuroglioma cells and is also effective for high blood pressure and inflammatory diseases. However, the effect of veratramine on prostate cancer had not been studied before.
The research team led by Choi Seong-gyun applied veratramine to prostate cancer cells and identified the concentration at which it inhibits the cells' biological functions. They confirmed that veratramine significantly inhibits the proliferation of prostate cancer. Furthermore, the experiments revealed that veratramine significantly reduces the cancer cells' survivability and mobility. The work is published in The American Journal of Chinese Medicine.
Through immunostaining, proteomics, and microarray analyses, the research team found that veratramine increases the expression of ATM/ATR, a DNA damage-related protein in prostate cancer cells, and suppresses the expression of the Akt protein involved in cancer cell proliferation. Additionally, when veratramine was administered to immunodeficient mice with prostate cancer, both the tumor size and the expression of tumorigenic proteins significantly decreased without any toxic lesions in the parenchymal organs.
Choi Seong-gyun, Director of the DGIST Core Protein Resources Center, stated, "This research lays the groundwork for developing effective substances that can overcome the limitations of existing treatments using island wildlife extracts. We will take the lead in constructing a utility database for various effective substances from island wildlife extracts for different diseases through active joint research between DGIST and the Honam National Institute of Biological Resources."
More information: Hee-Yeon Kim et al, Veratramine Inhibits the Cell Cycle Progression, Migration, and Invasion via ATM/ATR Pathway in Androgen-Independent Prostate Cancer, The American Journal of Chinese Medicine (2023). DOI: 10.1142/S0192415X2350060X
Provided by Daegu Gyeongbuk Institute of Science and Technology (DGIST)
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