A newly developed antibody has halted the growth and spread of aggressive prostate cancer in preclinical tests, raising hopes for a more targeted way of treating metastatic disease without the side effects that have hampered earlier attempts to block the same cancer-driving pathway.
Researchers from Umeå University in Sweden and international collaborators focused on a signaling pathway involving transforming growth factor beta, or TGFβ.
This pathway is a tricky one. Cells use TGFβ signaling like a messaging system. In healthy tissue, it helps regulate cell development, tissue repair, immune responses, and other essential functions. But in advanced cancers, it can be hijacked to help tumor cells invade, migrate, and metastasize.
“Previous attempts to develop inhibitors of TGFβ signaling in cancer, using TGFBR1 kinase inhibitors, have so far not been successful, partly because this treatment is shutting down all TGFβ signaling,” Maréne Landström, Professor of Pathology at Umeå University and the study’s senior author, told Refractor.
TGFβ molecules signal cells to regulate processes such as cell development, tissue repair, and immune responses by binding to cell-surface receptors, one of which is TGFBR1.
TGFBR1 has an enzyme-like section called a kinase, which works a bit like an on-switch. It adds chemical tags to other proteins, which passes the message deeper into the cell. A TGFBR1 kinase inhibitor is a drug designed to block that receptor’s internal signaling activity, interrupting the downstream TGFβ message.
TGFβ’s double role in regulating healthy and cancer cells has made it an attractive but difficult cancer treatment. Blocking too much of it can interfere with processes the body actually needs. Rather than blocking TGFβ signaling wholesale, the treatment developed by the researchers, called mAbF11, targets a more specific cancer-driving event.
In aggressive prostate cancer cells, an enzyme called ADAM17 cleaves the TGFβ type I receptor, known as TβRI. That cleavage releases an intracellular fragment, TβRI-ICD, which moves into the cell’s nucleus and helps switch on programs linked to invasion and metastasis. In simpler terms: the receptor is cut, the loose fragment heads into the cell’s command centre, and the cancer becomes better at spreading. mAbF11 is designed to stop that cut from happening.
The study was done using mouse models of metastatic castration-resistant prostate cancer, an advanced form of the disease that no longer responds to hormone-lowering treatment. The researchers found that high expression of TGFBR1, the gene encoding TβRI, was associated with poorer survival in two independent groups of patients with metastatic castration-resistant prostate cancer. TGFBR1 expression also correlated with ADAM17 expression, supporting the relevance of the cleavage pathway mAbF11 is designed to interrupt.
“We think that high expression of TGFBR1 could become a biomarker for identifying patients that are most likely to benefit from the new treatment strategy with mAbF11,” Landström said.
In preclinical mouse experiments, treatment with mAbF11 reduced tumor growth and metastasis in a dose-dependent manner. Importantly, it did so without noticeable effects on body weight, heart function or the diameter of the proximal aorta – safety signs of considerable interest because broader TGFβ-targeting approaches have previously raised cardiovascular concerns.
“TGFβ signaling is important for regulating differentiation of cells in the heart, and vessels like [the] proximal aorta,” Landström explains. “TGFβ signaling is also important for protecting us against cancer as it maintains homeostasis of epithelial cells and controls the immune response.”
The researchers also compared mAbF11 with docetaxel, a standard chemotherapy used in metastatic castration-resistant prostate cancer. Docetaxel reduced tumor volume and weight in the mouse model, but the study had to be terminated early in the docetaxel group because eight of 16 mice experienced severe body-weight loss. By contrast, mAbF11 showed similar anti-invasive effects in the lab and inhibited tumor growth and metastasis in vivo without those noticeable side effects.
Still, Landström cautions against interpreting the work as showing that mAbF11 could replace chemotherapy.
“The comparison was done as docetaxel is regarded as a ‘gold standard’ therapy for patients with metastatic castration-resistant prostate cancer,” she said. “We wanted to secure that the combination of treatment with mAbF11 and docetaxel was possible to do. It is too early to claim that treatment with mAbF11 could replace docetaxel or to plan if future treatment strategies should be given in sequences.”
That caution is warranted. The findings are certainly promising, but they are still preclinical. The work was performed in immunodeficient mice, meaning the researchers could not determine how mAbF11 might interact with anti-tumor immunity in a fully functioning immune system.
That will be an important next question, especially because TGFβ is known to suppress immune responses against cancer cells. If mAbF11 can block the cancer-promoting branch of TGFβ signaling while leaving more normal signaling intact, it could potentially pair well with immunotherapies. But that remains to be shown.
“This is an important question to resolve,” said Landström. “We would like to perform a combination study with mAbF11 together with checkpoint inhibitors or other immunotherapies, in [a] suitable syngeneic mice model.”
A syngeneic mouse model is an experimental setup in cancer research where mouse-derived tumor cells are implanted into a host mouse of the same genetic strain. Because the tumor and host are genetically matched, the host mouse’s immune system remains fully functional and doesn’t reject the tumor.
The researchers also tested mAbF11 beyond prostate cancer, using models of triple-negative breast cancer. In those experiments, the antibody reduced invasion in the lab and significantly lowered the number of lung metastases in mice that had had cancer cells injected into the mammary fat pads. The results suggest the approach may have relevance in other aggressive solid tumors.
That makes the approach potentially broader than prostate cancer alone, although much more work will be needed before it reaches patients. Safety studies are still required, and any future treatment would need regulatory approval before clinical use.
For now, the most important part of the study may be its precision. Instead of trying to silence a powerful biological pathway entirely, mAbF11 appears to block a specific malignant detour, the cleavage event that helps cancer cells grow, invade, and spread.
“The new drug has been developed to prevent metastasis,” Landström said in Umeå University’s press release. “We are very pleased and proud that we have been able to identify the mechanisms that drive cancer cell growth, invasiveness, and metastatic spread.”
The study was published in the journal Signal Transduction and Targeted Therapy.
Source: Umeå University
Fact-checked by Mike McRae
