Professor Daniel Tenen, who has devoted his research career to searching for a cure for cancer, has found an “ideal target”. It’s a gene called SALL4.
“I think it is the best target in cancer,” says the medical oncologist turned researcher who divides his time between two laboratories – one at Harvard in the U.S. and the other in Singapore.
The Senior Principal Investigator, Cancer Science Institute of Singapore and Professor of Medicine at the National University of Singapore spoke to the Leukaemia Foundation about SALL4 when he was in Brisbane for the New Directions in Leukaemia Research conference.
“My lab in Singapore works very closely with Li Chai’s lab in Boston on SALL4. She has worked on SALL4 her entire scientific career, and I joined up with her to work on solid tumours, such as liver cancer, because it is important in Asia. However, the principles are similar to those for leukaemia.”
Prof. Tenen and Dr Chai, an Associate Professor at Brigham and Women’s Hospital, Harvard Medical School, are looking for a “really good drug” to hit this target, and once a therapy is found, he believes it could be used to treat around one-third of all cancer patients immediately upon diagnosis, as well as 80-90% of people with acute myeloid leukaemia (AML) and some of the B-cell leukaemias.
Prof. Tenen, who describes himself as a “fundamental researcher”, has not treated a patient since 1983 yet, he says, the primary drugs he used then to treat younger patients with AML are the same drugs of choice for younger patients today.
“We do have other treatments for old people like me. They are good, but there is a long way to go,” says Prof. Tenen, who is a leader in gene regulation in both normal cell development and cancer.
He studies what turns genes on and off, which is important in both normal cells and cancer cells where the genes are turned on or off the wrong way. A large part of his focus is on leukaemia, and he has been doing basic research on this form of blood cancer, particularly AML, “for years”.
What SALL4 is and what it does
“I’m trying to understand how the SALL4 gene is expressed, and how it works,” explains Prof. Tenen, who also is head of the Blood Program of the Harvard Stem Cell Institute and Professor of Medicine at Harvard Medical School in Boston.
“It is one of the critical genes that make embryonic cells – the stem cells that divide, turn into other cells, and renew themselves.”
“SALL4 is really important for your early development. It is expressed in the embryo and the foetus and then, when you get to be an adult, it is turned off in most of your tissues. You do not need it anymore.”
“When it gets re-expressed, in about a third of human cancers, it contributes to the cancer cells’ survival. In these patients, SALL4 is turned on and it makes cancer cells keep replicating and not turning into the cells you need.”
“That’s what cancer is,” says Prof. Tenen, “and most human cancers are not dividing faster, they are just not in control.”
A lot of traditional cancer drugs affect the ability of cells to divide. And the major toxicities of traditional chemotherapy, such as your hair falling out, diarrhoea, nausea, and a drop in your blood counts, occur because the normal stem cells in your gut, hair, and blood are dividing faster than most of the cancer cells the drugs are trying to kill, he said.
This means the normal cells die before the cancer cells die.
“Scientists are always talking about how cancer cells proliferate, which means divide, and that’s a relatively minor component of human cancer,” says Prof. Tenen.
He mentioned that an Australian researcher, Professor Andreas Strasser, whose research the Leukaemia Foundation has funded in the past, “works on how cells die and that is more important than how cells divide in cancer”.
Developing a drug to target SALL4
“If you get rid of SALL4, which we can do experimentally in cancer cells that have it, the cancer cells die,” explains Prof. Tenen.
“So you could treat the people who express it with a SALL4 drug and you would not affect most normal cells. To me that is the ideal cancer drug – one that harms cancer cells without hurting normal cells.”
We’re trying to find things that destroy SALL4 but not other genes.
“SALL4 is only in the cancerous tissues and that is why it is a good target if you could specifically only affect it.”
Prof. Tenen said there are two ways to get rid of SALL4, which he describes as “this bad guy”.
“One is, you destroy it, and one is, you block its interaction with another protein,” and he said he has “a couple of compounds that look like they can destroy this bad guy”, for which his research team has preliminary patents and applications.
“You also want to find things that will not destroy the other good guys [normal cells] – that’s still at the early stage.”
One compound he’s “trying to develop into a real drug” is based on a drug candidate developed by his youngest daughter, Nicole, when she worked in the laboratory of Dr Chai.
“The irony with SALL4 is that drug companies generally do not like our target because it is not on the surface of the cell. SALL4 is in the nucleus, so it is harder to get to, not impossible, but harder,” Prof. Tenen explains.
“Most cancer drugs, even the ones you can take as a pill, start as something you inject. Yet drug companies also want a drug that is soluble – that you can take as a pill.”
“Another aspect of SALL4 is that it is not mutated in cancer. It gets turned on and there is more of it than there should be, so it is harder to study than a gene that is mutated, which we can sequence easily and detect easily in cells,” says Prof. Tenen.
Different proteins have different lifespans and SALL4 has a long lifespan, so another potential approach in the development of a therapy is to use a compound that interacts with SALL4, “causing it to degrade and go into the body’s natural garbage can faster”.
“We have some compounds we have screened for that, but more work is needed for them to be soluble enough to be a drug that has a long life in your blood,” says Prof. Tenen.
There is a different way to target SALL4, he said, because of its interaction with another protein, which, if blocked means SALL4 loses its ability to “promote the cancer cells to proliferate and divide and expand”.
“We have a peptide that will do that, and it has the effect of making normal cells work better and also kills SALL4.”
That is a really good drug because it makes the good guys better, and it makes the bad guys worse.
But Prof. Tenen said drug companies “do not want to touch a peptide”, mainly because it has to be injected.
The quest to fund further SALL4 research
The next step in Prof. Tenen’s research into SALL4 requires funding of $20 million.
“That’s the typical cost for taking what we call an early lead compound and getting it into the form where we could actually do a clinical trial in people. That will take two to three years and we’ve been talking to investors for about 10 years on this,” he says.
“We have talked to dozens and dozens of investors and companies. Because SALL4 is in the nucleus, not the surface of the cell, and because it is not mutated – it is too hard for them.”
“We had a $5 million investment by some Chinese investors, but the intellectual property and legal agreements at multiple institutions took over a year, and the investors said they could not wait any longer. I do not blame them, so, we keep trying.”
A drug that targets the SALL4 gene could be used to treat a third of all cancer patients at the start of their treatment, when they first present, according to Prof. Tenen.
He also said SALL4 may be turned on in people who do not express the gene when they are first diagnosed with cancer because, “when you treat cancers with other drugs, they evolve. They’re very smart, and they mutate”.
Understanding what turns the SALL4 gene on
Prof. Tenen is also interested in the biology of SALL4 – how it gets turned on, which is basic science.
“There is a condition called myelodysplastic syndrome (MDS) which means your bone marrow is not working right, and older people like me get it,” explains Prof. Tenen.
“One of the best treatments for MDS are de-methylating agents [azacitidine and decitabine] which alter the DNA. These work pretty well and are pretty much standard of care, particularly for older patients, but we do not know exactly how they work.”
“We’ve made some very interesting discoveries about demethylation,” says Prof. Tenen, and Li Chai and he had a recent New England Journal paper published on their findings that “demethylation can turn on a bad gene that does bad things, and we know which part of the SALL4 gene gets demethylated to cause it to turn on”.
“We think physicians who are treating with demethylation therapy should monitor the SALL4 levels [of their patients], because if it goes up, the really scary thing is… even patients who have responded to demethylation therapy and their blood counts are normal and they are feeling good …if you follow their course, they are likely to relapse and die.”
Professor Tenen said discovering a drug for SALL4 “would be amazing” and a priority would be getting it to clinicians and to patients.
Prof. Tenen seeks to study what others aren’t
As a basic scientist, Prof. Tenen says, “I just want to figure out how things work, but I have an eye on how they might be applied”.
“That is the nice thing about having a physician’s background and a specialist background – in the back of my mind, I am thinking about how something might be beneficial.”
“I like to study things that other people are not studying. I want to do something different. It’s more fun.”
His interest centres on how a kind of white acute myeloid leukaemia blood cell differentiates – changes from an immature cell into a neutrophil.
“I want to know how they normally develop, because maybe then we could figure out what goes wrong in acute myeloid leukaemia – that’s the lineage I really got interested in,” he says.
“We discovered there was one protein or one gene, called a transcription factor, which means it dictates how genes are expressed by interacting with DNA to turn genes on or off, and that is critical for the development of neutrophils. That gene turns out to be mutated in acute myeloid leukaemia.”
What does that have to do with leukaemia? We don’t know yet, but this is how you discover fundamental things. We’ll find out.
“There’s a neat technology now called single cell. People used to study collections of cells, now they’re looking at single cells and asking what they’re doing.”
“There are lots of cell therapies, simple things like transfusions, and now people are really excited about using immunotherapy, where we modulate immune cells to attack a cancer where normally your body does that.”
“People with acute myeloid leukaemia used to die because they didn’t make enough red cells to carry oxygen. They don’t die of that anymore because you can transfuse them.”
“What they do die of is the lineage I have studied, which makes neutrophils.
“A neutrophil is like the foot soldier in an army. It goes out in your blood and dies in 24 hours. While it is in the blood, if it sees a bacterium, it’s going to eat it or kill it, and it is likely to do it by suicide.
“It is a really stupid cell, but if you do not have them, you are going to die of infection, and most patients with AML these days die of infection because they do not make neutrophils. It is hard to transfuse neutrophils because they tend to die in a few days. You can’t store them.
If you put them in, they’re gone.”
Prof. Tenen has discovered another gene which is mutated in acute myeloid leukaemia, which affects the production of macrophages – also a white cell that “is basically a garbage bin that eats up a lot of stuff including bacteria”.
Background on Professor Daniel Tenen
It was during Prof. Tenen’s third year as a science undergraduate at the University of California, Los Angeles that the discovery of enzymes that could cut and paste DNA, made genetic engineering possible.
“This was the dawn of molecular biology, and I got very excited about that,” says Prof. Tenen.
He was interested in science, molecular biology and “how genes work”.
“I wanted to do molecular biology. I wanted to cut DNA, study it and figure out how it worked.”
When his favourite professor at UCLA told him about a physicist, Walter Gilbert* who was working in this area at Harvard, he applied and was accepted to Harvard Medical School in Boston.
“Eventually, in my third year in medical school, I worked in Wally’s lab, so then I was hooked,” said Prof. Tenen.
“I love what I do because I love science, and it is more exciting now than ever. We are doing some really weird stuff and it is so much fun. I am not going to retire until I am dead.”
*Walter Gilbert, a Professor Emeritus at Harvard University, received the Nobel Prize in Chemistry in 1980 for developing a method of rapidly sequencing DNA – a discovery that helped scientists map the entire human genome.
