By Marta Lora
Last September, Galina Botchkina, a cancer researcher at Stony Brook University, eagerly awaited tissue samples from a patient with liver cancer who had undergone surgery. Previously, the patient had received chemotherapy, but that didn’t stop the cancer from spreading to other organs.
Galina hoped the sample would add new evidence to a growing body of research that there are in fact not one, but two kinds of cancer cells and that one kind is so powerful that it can survive traditional cancer treatments. If true, the theory could explain why so many tumors reoccur after chemotherapy and radiotherapy.
It was about 9pm by the time the samples arrived and she was the only researcher in the lab. Examining the tissue under a microscope, Botchkina was crestfallen. “I was upset that all the cells seemed dead. I was so tired that I didn’t even bother to throw them away,” she said. “I just left them in the incubator.”
Two days later, she decided to take one last look. In the middle of a cluster of dead cells, she found five or six cells that were still alive. They had survived the chemotherapy.
“I had dual feelings,” Botchkina said recently. “It was good for our research, but it meant that this particular patient most likely will have cancer recurrence.”
Botchkina’s research focuses on finding a new drug targeting prostate and colon cancer stem cells to prevent such reoccurrence. The National Institutes of Health already has awarded Botchkina’s lab a $370, 000 grant to investigate the cells.
In the 1990s, researchers first found evidence that cancer cells were not homogeneous and that there were two different types of cancer cells in human tumors. The newly identified type of cells only represented a small subset of the whole population of cancer cells, but they could survive traditional cancer treatments and propagate the disease to other tissues, making tumors grow back.
Scientists named the cells ‘cancer stem cells’ because they have similar properties to ordinary stem cells, but are malignant.
Since then dozens of laboratories worldwide have been studying the cells. According to the American Cancer Society, one fifth of breast cancer patients will suffer a case of recurrence within the first ten years after treatment. For prostate cancer patients, the chance of having a recurrence after treatment can be as high as 25 percent.
In New York State, Botchkina and her team are not the only ones interested in cancer stem cells. Memorial Sloan-Kettering Cancer Center, New York University, Rockefeller University and Cold Spring Harbor lab are all pursuing research in the area. Most labs are probing the characteristics of the cells. But a few of those laboratories, like Botchkina’s at Stony Brook, are also focusing on the creation of new therapies that might destroy cancer stem cells or suppress them.
The future impact of cancer stem cell research is so promising that the Empire State Stem Cell Program (NYSTEM), the second largest government-financed stem cell program in the country, awarded $16.4 million for cancer stem cell research in New York State last year, funding more than 20 projects.
Over the last year, pharmaceutical companies worldwide also started investing in the field. Verastem, a newly-formed company, which is in the early stages of a clinical trial for a drug targeting breast and ovarian cancer stem cells, had a total market value of $200 million when the company started trading.
Galina Botchkina has been working on cancer stem cells since 2005, when Iwao Ojima, the director of the Drug Discovery department at Stony Brook University, decided to create a laboratory to investigate the new type of cells.
“I started because of personal motivation,” she said. “My mother was dying from breast cancer.”
Botchkina emigrated from Russia 23 years ago with her family. She was an associate professor at Stony Brook University Medical Center when her mother was first diagnosed with cancer in 2005. Although physicians treated her mother with their most advanced therapies, Botchkina realized they were not effective. She had been working in the field of cancer research for more than ten years and she had heard about the controversial theory of treatment-resistant cells.
Her mother’s case, she said, prompted her to change her research focus to cancer stem cells, even though she couldn’t save her mother’s life. Her mother died in 2007.
“If nothing is working right now, any other hypothesis is reasonable,’ Botchkina said.
Last year, she found a chemical compound that was able to destroy cancer stem cells, but it also affected healthy cells. She didn’t give up. She began the search for other compounds.
Eight years before Botchkina and Ojima started their Cancer Stem Cell Research laboratory, two researchers at the University of Toronto found the first conclusive evidence for cancer stem cells.
In 1997, Dominique Bonnet and John Dick discovered a group of cells in leukemia tumors that were very similar to stem cells, but with distinct molecules that make them divide non-stop. They were cancer stem cells. Every type of cell has particular molecules that make it unique. These molecules allow researchers to identify different types of cells and investigate mutations and abnormal behaviour.
Since then, cancer stem cells have been identified in most fluid and solid tumors.
Although researchers have been able to prove that these types of malignant cells are present in most tumors, they still don’t know how the cells arise.
“They probably arise from normal stem cells or other progenitors,’” said Robert Weinberg, a founding member of the Whitehead Institute for Biomedical Research at MIT.
Stem cells can become malignant because of a gene mutation. Once stem cells become cancer stem cells, they survive traditional treatments like chemotherapy and radiotherapy. “If you give radiation to your body, stem cells will survive,” said Bayard Clarkson, a pioneer in cancer and researcher at the Memorial Sloan-Kettering Cancer Center in New York City.
Cancer stem cells can produce regular cancer cells or other cancer stem cells. As a way to defend themselves against chemotherapy, they produce more cancer stem cells instead of normal cancer cells. Tumors will likely grow back, but this time they will be untreatable because the population of treatment-resistant cells will grow larger.
“They can survive chemotherapy and radiotherapy and they can generate new tumors,’ Weinberg said.
Although there is now enough evidence that cancer stem cells are mostly responsible for cancer recurrence, a controversy erupted when studies first appeared.
“Ten years ago, nobody believed me,” said Clarkson, who has been working his whole life in the field of cancer. “They thought I was crazy. Even now that there’s enough evidence, some of my colleagues still refuse to call them like that. They say cancer-originating cells.”
The major controversy was that all the past studies relied largely on transplanting human cancer cells into mice and cell cultures, two artificial environments. But this past summer, two studies resolved any debate.
Last August, a study from a group of researchers at the University of Texas focused their research on brain tumors. They were trying to find specific markers of cancer stem cells in gliobastoma, a very aggressive type of brain cancer. They discovered that a small group of cells inside the tumor had a specific molecule that made them distinct from most cancer cells. The cells without the molecule were killed with chemotherapy, but the cells with that marker survived.
The same month, another study from the University of Brussels was published in Nature. The research on skin cancer found that cancer cells have two different patterns of division. Some cells produce similar cells before diminishing and other cells keep producing new cells without dying. The latter are cancer stem cells.
The process of studying cancer stem cells and possible drugs targeting them is long and tedious.
For Botchkina and her team, everything starts after they receive tissue from a patient with colon or prostate cancer that undergoes surgery. Right after that, her team needs to cut the tissue and isolate ‘normal’ cancer cells and cancer stem cells.
“Then it’s a real struggle,’ she said. “Cancer cells usually don’t like to grow in artificial cultured conditions.”
However, Botchkina’s team was very fortunate because their colon and prostate cancer tissues survived in culture and the cells kept dividing indefinitely.
Once cells adapt to their new environment in Petri dishes, researchers can start experimenting with compounds that could possibly destroy the cells. The Chemistry Department at Stony Brook provided Botchkina’s lab with dozens of compounds and natural chemicals. One of those chemicals is an anticancer drug that was modified by Ojima’s laboratory to create what researchers call a ‘third-generation taxoid,’ a drug derived from natural chemicals in yew trees. The new therapy can target specific malignant cells leaving the healthy cells intact. Every compound is tested several times using different concentrations, different exposures times and different combinations.
But finding a compound strong enough to destroy cancer stem cells is just the beginning. Before a new drug is approved by the FDA, it is required to be tested first in mice and then in humans in a clinical trial.
It usually takes between five and ten years to develop a new therapy for cancer.
At New York University Langone Medical Center, some researchers decided to take a different approach.
A group of scientists, led by Claudio Basilico, is studying how cancer stem cells are activated in bone cancer. “They are in a quiet state,” Basilico said. “There’s an agent that activates them and they are very malignant once activated.”
Basilico’s team has already tested thousands of compounds looking for the right one to keep the cells asleep. “Until we find the way to completely destroy them, we need a way to keep them quiet,” Basilico said.
His team is still working on the first steps. “We are still doing culture,” he said.
According to NYSTEM, there are more than a hundred scientists doing stem cell research in New York State and about 25 percent of those investigators focus their research on different aspects of cancer. Many researchers study the fundamental aspects of stem cell biology, how the cells grow and how they divide.
The National Institutes of Health (NIH) provides substantial funding to individual laboratories, between $200, 000 and 400, 000 per year for up to five years. Because of the lack of conclusive data in the past regarding cancer stem cells, funding is sometimes hard to obtain and awards are relatively modest. The NIH usually provides only between $100,000 and $200, 000, normally for just one to two year
Because of the potential impact of cancer stem cells research, some pharmaceutical companies already have shown interest in this field, each focusing on a different type of cancer.
Oncomed, a NY-based pharmaceutical company, is probably the closest to developing a new drug .
Last year, company researchers completed a Phase I clinical trial, testing the drug on a small group of patients to evaluate its safety. They tested Demcizumab, a drug for pancreatic and non-small cell lung cancer (NSCLC) that regulates how cells communicate. They tested the drug on 55 cancer patients who had already received chemotherapy. Early results indicated that 64 percent of the patients who participated in the clinical trial showed some tumor shrinkage or no further growth.
Verastem is the only publicly-traded pharmaceutical company specializing in cancer stem cells. Of the more than 300,000 compounds that scientists screened, less than 0.5 percent were able to kill the cells. The Massachusetts-based company focuses its research on creating drugs that control cell migration in solid tumors, the cause of metastasis.
“We know that ninety percent of cancer patients die from metastasis,” John Clarke, a member of Verastem Board of Directors, said last month at the BIO Investor Forum in San Francisco. “We believe that new drugs targeting cancer stem cells in combination with traditional drugs will be able to eliminate these cells.” Their company’s most advanced drug candidate is still in the early stages of a clinical trial.
There are still many questions that scientists need to answer about cancer stem cells before developing an effective new therapy: the mystery of their origin, the way that they are activated, and why they become malignant.
While researchers search for the answers to those basic questions, Botchkina and her team keep working on a new drug that in combination with traditional therapies could inhibit cell division. Based on previous studies, she decided to mix the third-generation taxoid, provided by Ojima’s lab, with curcumin, a substance found in the spice turmeric and largely consumed in Asia. Some studies suggest that this natural chemical may prevent some types of cancer because of its anti-inflammatory properties.
So far, Botchkina’s research shows that the combination of these two compounds impedes the ability of cancer stem cells to divide. She already has filed a patent on the use of the two compounds and is now preparing the paperwork to start a clinical trial. But Botchkina’s team will still have to wait a few more years to fully develop any new treatment specifically for colon and prostate cancer.
“This is a very long path,” Botchkina said.