Understanding and influencing the tumor microenvironment
Understanding and influencing the tumor microenvironment
For a long time, cancer research was all about investigating the genetic traits of cancer cells. But in the past couple of decades, it gradually dawned on researchers that the key to more effective cancer therapies might lie in the complex structures surrounding these cancer cells. VIB scientists have been investigating the tumor microenvironment for many years, and have discovered multiple ways to fight tumors, including starving them to death, "stealing" their sugar supply, and boosting their destruction using immunotherapy.
The innovators
Starve tumors to death
In 1996 – when VIB had just been founded – one of the research focuses of Prof. Peter Carmeliet was the essential role of angiogenesis – the growth of new blood vessels – in cancer development. Angiogenesis plays an important positive role in the development of fetuses and wound healing. However, the process can also be dangerous when abnormally upregulated, as the increased blood supply helps tumors to grow more rapidly.
About fifteen years ago, Carmeliet and the Leuven-based company ThromboGenics – now Oxurion – developed an antibody that blocks a molecule called placental growth factor (PlGF), responsible for such abnormal angiogenesis in tumors. "By reducing the blood supply, we can literally starve a tumor to death," Carmeliet explains. "Since PlGF has no function after birth, except for creating blood vessels to grow and spread cancer, there was nothing to stop us from targeting it. By starving the tumor, it becomes more vulnerable to destruction by the body's own immune system and chemotherapy, and finds it harder to spread to other parts of the body."
This breakthrough marked the start of an ever-increasing focus on the tumor microenvironment. In 2009, professor Massimiliano Mazzone and co-scientists successfully targeted a certain class of proteins which regulate how oxygen is delivered to a tumor: PHD proteins (published in Cell). Enhancing the oxygen supply to a tumor allows therapies to be more efficient and makes metastasis, a process in which cancer cells spread to other body parts, less likely to occur. In the following years, the team targeted other proteins – such as HRG and neuropilin 1 – in order to inhibit angiogenesis and metastasis.
Oncurious: developing next generation immuno oncology assets
In 2015, VIB and Oxurion set up a joint venture – Oncurious – to accelerate the development of an anti-PlGF therapy for the treatment of medulloblastoma: a rare, life-threatening brain tumor occurring mainly in children and adolescents. Two years later, the European Commission confirmed its support for the drug’s development. In that same year, Oncurious acquired a unique portfolio of next-generation immuno-oncology assets from VIB, based on seminal work originating from the labs of professors Massimiliano Mazzone, Gabriele Bergers (VIB-KU Leuven Center for Cancer Biology) and Jo Van Ginderachter (VIB Center for Inflammation Research, VUB), resulting in an exciting pipeline of next-gen immuno-oncology drugs that target a broad spectrum of cancers.
Stealing a tumor's sugar
Meanwhile, a particular type of immune cells called macrophages crossed the path of professor Mazzone. Their properties had already been studied extensively, but it remained unknown as to whether changing the macrophages’ metabolism would impact their functions. Mazzone and his team managed to reveal that cancer cells "hijack" the macrophages to enter the patient's bloodstream and spread to other organs. Sugar plays an important role in that process.
Mazzone: "In some way, you can compare a tumor to a child: too much sugar makes it hyperactive. Regarding tumors, this means a chaotic, defective blood vessel network quickly forms, promoting the growth and spread of cancer cells. That's why we tried – and managed – to attune the macrophages. The key is in making them more prone to "stealing" sugar from the cells forming the tumor’s blood vessels. As a result, these blood vessels will be structured more tightly, creating a strong and organized blood vessel barrier around the tumor which prevents the cancer cells from spreading to other organs."
Enter immunotherapy
Anti-angiogenic therapy and the emerging field of immunotherapy meet in a study conducted by the lab of professor Gabriele Bergers, together with the University of California and the Swiss Institute for Experimental Cancer Research. The successful combination of both therapies results in the growth of specialized blood vessels that deliver cancer-fighting immune cells to the tumor, potentially leading to more effective treatments and longer survival periods.
Montis: regulating immune cell influx into tumors
In 2020, VIB, KU Leuven and Droia Ventures launched Montis Biosciences, a spin-off aiming to exploit the interactions between macrophages and the vasculature in order to ensure a strong influx of fresh immune cells into the tumor. With 8.4 million euros in seed financing and the support of VLAIO, the potential of therapeutic targets based on the groundwork at VIB's Center for Cancer Biology is being investigated.
“It gradually became clear to us that rather than destroying the blood vessels, we can use them to herd the correct immune cells to the tumor and get much more potent and sustainable effects," confirms Carmeliet. "Tumors tend to find a way to evolve and build up resistance against specific therapies,” adds Mazzone. “With our research into the tumor microenvironment, we're rapidly gaining valuable insights about the common ground of tumors, which will allow us to develop stronger therapies that are applicable to different tumor types. The foundation of Montis Biosciences is a major step forward, but this is only one path we're following to exploit the tumor microenvironment for cancer therapies."
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