Research  >  About SRI  >  Publications  >  SRI Magazine  >  SRI Magazine 2016  >  Target: Cancer  >  Overcoming treatment resistance in cancer
Share:  
|

Table of contents

SRI Magazine 2016

SRI Magazine 2016

Overcoming treatment resistance in cancer

Therapy can simply stop working, to devastating end. New research gets closer to why

Imagine you have cancer. You go through multiple rounds of treatment, enduring nausea, fatigue and other sickening side effects. Nothing works. The cancer continues to grow.

Now imagine yourself as another patient with cancer. Your treatment is working. The tumour is shrinking. Your doctors are optimistic. Then, one day, you learn the treatment has stopped working. The tumour has started to grow back. You try other drugs, but it’s always the same: they work for a while; then, inevitably, they lose their effectiveness and the cancer rebounds. These scenarios describe treatment resistance. In the first case, the cancer cells have intrinsic resistance to the treatment—they are resistant from the get-go without previous exposure to the drug. In the second scenario, the cancer develops resistance to the drug after being exposed to it. Think of this acquired resistance as cancer cells evolving in response to a danger in their environment. For many people with cancer, these scenarios require no imagination. It is their reality.

At Sunnybrook Research Institute (SRI), Dr. Robert Kerbel, a senior scientist, is studying the biology of treatment resistance to find ways of overcoming it. “The mainstay of cancer treatment to this day is still chemotherapy,” he says. “There are certain cancers where a high proportion of patients respond to chemotherapy, and there are a couple of cancers that are just notoriously resistant to chemotherapy drugs. One of them is kidney cancer. It just doesn’t respond.”

Renal cell carcinoma (RCC) is a common type of kidney cancer. Roughly 90% of all kidney cancer is RCC. A major gain in the treatment of advanced RCC has been the approval of four therapies that function as tyrosine kinase inhibitors (TKIs). These drugs target a growth factor protein that enables cancer cells to attract and build a blood supply to the tumour, thereby allowing it to grow bigger. By blocking the protein, TKIs deprive the tumour of nutrients and prevent its growth.

These TKIs are not, however, a cure-all. About one-fifth of patients with kidney cancer are intrinsically resistant to TKIs. One gets the sense that these are the patients that inspire Kerbel’s research.

Recently, Kerbel and his team showed that pazopanib, one of the approved TKIs for advanced RCC, has potent anti-tumour activity in TKI-resistant cancer cells when given in combination with the chemotherapy drug topotecan.

To do this work, the researchers created the first preclinical model for metastatic RCC in which the cancer had spread from the kidneys to other organs. Using this mouse model, when they tested pazopanib alone, they found the drug had no effect on tumour growth, disease spread or overall survival. These cancers were innately immune to pazopanib.

In contrast, when the researchers gave pazopanib with topotecan, the tumours shrank in size and spread to fewer organs compared to treatment with either drug alone. Overall survival was also significantly extended. They observed these effects when the drugs were given in two scenarios: early on to treat the primary tumour and after the cancer had spread extensively from the kidney to other sites.

“It’s been hard to find any other agents [to give alongside TKIs] because of toxicity. There are really no good combinations,” says Dr. Georg Bjarnason, a senior scientist at SRI and an oncologist at Sunnybrook’s Odette Cancer Centre. Bjarnason specializes in kidney cancer and worked with Kerbel on the study. The researchers overcame the issue of toxicity by lowering the dose of topotecan given with pazopanib. “[This study] discovered a potentially new combination that can be active in tumours that seem to be intrinsically resistant,” says Bjarnason.

These results, which were published in 2015 in Science Translational Medicine, challenge the very notion of intrinsic resistance. “It really raises this [question] of whether the cancer cells are really truly resistant to TKIs,” says Kerbel. “Maybe there are also chemotherapy drugs [that], depending on the nature of the drug and the way it’s scheduled and dosed, might make a cancer that is generally thought to be intrinsically resistant not resistant.” The possibility of as-yet undiscovered TKI and chemotherapy drug combinations offers new hope to the 20% of RCC patients whose tumours are unresponsive to TKIs.

Kerbel’s research is also shedding light on how tumours become impervious to drugs following treatment. To study this question, he focused on a type of liver cancer known as hepatocellular carcinoma (HCC). The only approved therapy for advanced HCC is a TKI drug called sorafenib. Like the TKIs used to treat kidney cancer, sorafenib works mainly by inhibiting the process of new blood vessel formation, or angiogenesis. Without angiogenesis, the tumours starve and cease to grow. While sorafenib can prolong overall survival in patients with advanced HCC, it inevitably stops working because the tumours develop resistance.

In the drug-resistant tumours, the researchers were surprised to see that, instead of making new blood vessels, the tumours were co-opting—stealing, in effect—blood vessels from healthy neighbouring tissue.

Kerbel and his colleagues, including former PhD student Elizabeth Kuczynski, compared sorafenib-sensitive tumours with those that were sorafenib-resistant under a microscope. They saw a key difference that explained why the drug stopped working.

In the drug-sensitive tumours, the researchers could see signs of angiogenesis. On the other hand, in the drug-resistant tumours, the researchers were surprised to see that, instead of making new blood vessels, the tumours were co-opting—stealing, in effect—blood vessels from healthy neighbouring tissue in the liver to supply them with the oxygen and nutrients they need.

“That was a ‘Eureka!’ revelation moment for me,” says Kerbel. “It’s like an evolutionary selection pressure. [The tumours] are angiogenic at the beginning, but you’re sort of forcing them to switch to [using] the normal, existing [blood] supply.”

Because the tumours were no longer relying on angiogenesis to grow, sorafenib, an antiangiogenic drug, lost its effect. These results provide the first evidence for vessel co-option as the cause of acquired resistance to sorafenib in HCC. The study was published in April 2016 in the Journal of the National Cancer Institute.

The researchers also found that the sorafenib-resistant HCC cells had turned on a set of genes that enabled the tumour cells to be more mobile and invade adjacent tissues to steal their blood vessels.

As a next step, Kerbel is trying to figure out a way of overcoming acquired resistance by targeting the hijacked vessels themselves. “They’re not new blood vessels so antiangiogenic therapies won’t work,” he says. “But that doesn’t mean some other type of anti-vascular therapy won’t.”

Kerbel’s research is funded by the Canadian Breast Cancer Foundation, Canadian Institutes of Health Research, Israel Cancer Research Fund and Worldwide Cancer Research.