Ashok Venkitaraman
Description: Ashok Venkitaraman is a Professor of Medicine at the National University of Singapore Yong Loo Lin School of Medicine as well as Director of the Cancer Science Institute of Singapore and NUS Centre for Cancer Research.His research focuses on two main questions, what makes certain people more susceptible to cancer over others, and how can we delay cancer evolution in different tissues.In this episode we talk about the role of certain “chromosome custodian” genes that play a key role in safeguarding DNA integrity. Professor Venkitaraman expresses his optimism about the future of cancer research and the possibilities for both more holistic and targeted treatments.
Websites:
Publications:
Articles:
Scientists uncover a missing link between poor diet and higher cancer risk
Show Notes:
[0:00] Introduction
[3:29] Understanding Cancer
[6:36] Genetic Mutations in Cancer
[8:49] Targeting the Cell Cycle
[10:34] Novel Therapies for Slow-Dividing Cells
[11:33] Emerging Cancer Therapies
[14:43] Immune System Activation in Cancer Therapy
[16:07] Effects of Untreated Cancer
[18:03] Metastasis of Skin Cancer
[20:04] Treating Cancer Cachexia
[22:18] Genetic Predisposition to Cancer
[24:26] Genetic Interplay with Environmental Factors
[25:59] Impact of Aldehydes on Cancer Risk
[27:23] Natural vs. Synthetic Cancer Risks
[29:15] Exploring BRCA and Chromosome Custodian
[32:36] Gene Editing for Mutation Correction
[38:47] Focus on Prevention Over Treatment
[45:09] Potential of Natural Medicines
[48:41] Innovation Disparities in Cancer Research
[54:05] Traditional Chinese Medicines in Research
[54:31] Generation to End Cancer Hope
[56:06] Advice for Students in Cancer Research
Unedited AI Generated Transcript:
Brent
[0:01]
Welcome, Professor Ashok Venkitaraman . Thank you for coming on today.
Ashok
[0:04]
It's a real pleasure, Brent. Thank you for having me.
Keller
[0:07]
We'd love to start off by hearing a little bit more about your story,
how you got to NUS, and what got you interested in medicine and cancer science.
Ashok
[0:14]
Yeah, my career has been somewhat peripatetic in that I grew up in the United States.
I did med school in India, practiced as a doctor in India, before ending up
back in the United Kingdom to do my PhD and train as a researcher.
After that, I spent over 35 years of my career in Cambridge,
from the time I was a postdoc all the way until I was an established professor,
directing the Medical Research Council's cancer unit there, before this unbelievable
opportunity came by for me to, if you will, return to my Asian roots by coming
back to Singapore about two and a half years ago.
Brent
[0:55]
Yeah. What got you interested in studying cancer?
Ashok
[0:59]
Again, the story is a bit perhaps unusual. I didn't start out wanting to study cancer.
I actually started out training as an infectious disease physician and started,
of course, thinking about the immune system and how it counteracts infectious diseases.
Partway through my career, I was studying about how the immune system generates diversity.
In other words, how immune cells are able to recognize such a vast repertoire
of different antigenic substances.
Ashok
[1:37]
And when we were thinking about that problem, it was pretty clear that there
were multiple DNA rearrangements going on in the genome of immune cells,
lymphocytes, and I got interested in that mechanism and how it works.
In other words, controlled breakage and rearrangement of receptor loci in immunocytes.
At that time, this was in the mid-1990s, people, in fact, in Berkeley,
Mary Claire King and others in Seattle and others close to me at the Sanger
Institute in Cambridge,
were working on familial cancer genes.
And they cloned two genes, the breast cancer gene 1, BLCA1,
and the breast cancer gene 2, BLCA2, which were the first genes to be implicated
in inherited predisposition to this really common and important form of cancer.
Ashok
[2:38]
So the early studies published on BLCA2 in particular suggested to me that it
might have something to do with breakage and repair of rearranged gene segments in immunocytes.
So we quickly got together, a few postdocs, a PhD student, and myself in my
laboratory, and we decided to test that hypothesis.
Of course, three months later, we realized that hypothesis was completely wrong.
Wrong so we were kind of beholden to try and tackle the problem and that's what
led us into breast cancer genes inherited breast cancer susceptibility so as
you can see it was a bit of a segue at that point definitely.
Keller
[3:24]
And before we go more into depth on that particular gene could you just tell
[3:29]
Understanding Cancer
Keller
[3:27]
us a brief overview of what is cancer.
Ashok
[3:29]
Sure i guess the simplest way to describe cancer is cells behaving abnormally.
Cells which don't obey the normal rules which govern what keeps our cells intact
and, if you will, our bodies healthy.
So, for example, normal cells have a limit in the number of times that they
divide and proliferate.
Cancer cells seem to lose the checks and balances that impose this limit. it.
Normal cells typically undergo programmed cell death when they're called upon to do so.
Cancer cells seem to have forgotten how to do this, and they just keep dividing.
Finally, structures within the genomes of cancer cells, like telomeres,
which cap the ends of chromosomes,
again don't seem to obey the normal rules in normal cells and support almost
unending cell division in cancer cells.
So these are just a few of the examples in which cancer cells behave abnormally.
The other key factor in cancer is what gives rise to these abnormal behaviors.
In other words, what makes cancer cells different from normal cells?
Why do they behave this way?
And the answer is we've now come to understand that unlike most other diseases
in humans, cancer is a disease of genetic mutation.
Ashok
[4:57]
Many, many diseases, we inherit predisposition or even resistance to these diseases
because we carry something in our genes that encodes susceptibility or allows
resistance. Cancer is different.
Beyond susceptibility or resistance, cancer cells essentially evolve because
their genomes are constantly changing,
mutating, and these mutations are what confer abnormal behaviors on the cancer cells.
And so, genome mutation is, if you will, the driver of cancer in most tissues.
This is not absolute, of course, I'm simplifying, but by and large, it's the way it works.
Brent
[5:38]
Yeah. So, what causes most of those mutations?
Is it environmental factors, carcinogens, or is it predetermined genetic material?
Ashok
[5:48]
That's a great question, Brent. First, there is a really important role of environment.
It's been estimated that perhaps up to a third of different cancers are potentially
preventable if only we adjusted some of these environmental variables,
the best known, of course, being factors like smoking, which confers roughly
a 30-fold excess risk of lung cancer.
On the other hand, we also know that genetics plays a really important role.
In other words, we all inherit susceptibility or resistance to developing cancer in our genes.
So part of the origins of cancer is in our genes and part is in how our genetic
inheritance interacts with the environment.
[6:36]
Genetic Mutations in Cancer
Ashok
[6:36]
This has been extremely difficult to really pick apart.
A lot of the low-hanging fruit, for example, changes in genes which you inherit
and give you an extremely high risk of cancer, an example being mutations in
the breast cancer genes, BRCA1 or BRCA2, have more or less been identified.
But they don't fully explain why some people are more susceptible to cancer
than others, and we know that to be the case.
Instead, we think that for many of these individuals, many of us in other words,
there are certain genetic changes which may not give us a very high risk of
cancer, but somewhat increase our risk of cancer.
And we further understand that some of these genetic factors may interact with
environmental factors and that may compound, if you will, the risk of developing cancer.
So it's a complicated issue, but in my mind, it's one of the most important
unresolved issues concerning the genesis of cancer.
Brent
[7:38]
Yeah. And then one other thing, when you were mentioning the telomeres being
different, I know telomeres are being talked about in the aging space,
and like longer telomeres means like younger cells, for lack of better words.
What's the association with cancer and telomeres and lengths?
Ashok
[7:55]
That's another perceptive question, Brent. And the reason is we know that cancer
is primarily, not always, but primarily a disease of older people.
The risk of cancer goes up as you age. And one of the factors seems to be that
that gives enough time for mutations, which are the drivers of cancer, to accumulate.
Telomere shortening is also associated with aging,
and it's been speculated that some of the same factors that drive the accumulation
of mutations in our genomes may also contribute to the changes in telomeres related to aging.
In other words, there are really intricate relationships between cancer and
aging, including at the level of telomeres, that speak to, if not identical
causes, at least correlated or overlapping causation.
[8:49]
Targeting the Cell Cycle
Keller
[8:49]
Are we able to target different parts of the cell cycle when trying to prevent cancer?
Ashok
[8:56]
That's again an interesting question. I've got to stop saying this.
Keller
[8:58]
Don't I?
Ashok
[8:59]
All your questions are really good. Good. So, let me kind of pick that question apart a little bit.
The first part of the rationale here that you're speaking to is that cancer
cells divide differently, as I mentioned, from normal cells.
They're not subject to the same checks and balances.
So, yes, when cancer cells divide rapidly,
it is possible to target phases of the cell cycle in which they They predominantly
reside in order to, if you will, kill them, but not the surrounding normal cells.
So these would be, for example, phases of DNA synthesis, which cancer cells
will be undertaking at a far higher rate than, say, normal cells.
And in fact, many of the so-called chemotherapeutic agents, which have been
around for the last 30 or 40 years to treat cancer, work in that way.
Radiation hits dividing cells primarily.
Many of the chemotherapeutic drugs incorporate into DNA and prevent further replication.
Ashok
[10:06]
But it's pretty clear that division is not the only thing that differentiates
cancer cells from normal cells. I think we've discussed some of the differences.
What we do know, in fact, is that
in many advanced cancers, not all of the cells are dividing very fast.
Some of them are actually, if not quiescent, dividing quite slowly,
and it's quite hard to target some of these cells using therapies that simply target the cell cycle.
[10:34]
Novel Therapies for Slow-Dividing Cells
Keller
[10:34]
Are there any novel therapies that are coming out to try to find those slower dividing cells? else?
Ashok
[10:41]
Absolutely. I think the general trend over the last 10 to 15 years has been
to ask the question in a manner akin to what people did when they were thinking
about infectious agents like bacteria,
and ask the question, what distinguishes the biology of these organisms or cancer
cells from that of normal cells?
And through this understanding, can we find differences that generate molecular
targets that can be drugged or otherwise therapeutically addressed?
With cancer cells, the problem is, unlike bacteria, they actually arise from us.
And so the differences between us, normal cells, and cancer cells are not so
vast as, for example, with bacteria. So it's been a lot more difficult.
[11:33]
Emerging Cancer Therapies
Ashok
[11:28]
But that said, it's becoming increasingly clear that you can target cancer cells.
For lack of time, I'm just going to allude to a few of the conceptual.
Ashok
[11:40]
Ideas that have taken root. The first is that, as I said, cancer cells acquire mutations.
Some of these mutations change proteins at the cell surface or cause the expression
of proteins at the cell surface of these cancer cells that would not normally be expressed.
And so you can target these proteins with antibodies or therapeutic peptides
and similar therapeutic agents.
There are a number of very successful therapies that use this approach.
Ashok
[12:10]
Second is some of the changes that drive cancer are what I would call oncogenic
changes, by which I mean they're dominant and they push cell division or prevent cell death.
Some of these changes are also targetable, and people have discovered drugs
that target specific oncogenic drivers,
including surface receptors that drive cancer cell proliferation,
as well as intracellular molecules which are necessary for cancer cell proliferation.
These are more targeted because they are selective, obviously,
to the changes that have occurred in cancer cells, in oncogenes,
for example, and so would tend to spare normal cells.
The last approach, which has only recently taken root, is our recognition that
besides Besides dominant genetic events which drive the division,
survival, or lifespan of cancer cells,
there are also recessive genetic events.
In other words, loss of normal controls, where typically the control gene is
inactivated, not activated in cancer.
And these types of genes are called tumor suppressor genes. It's evident why
they're called this. and you have to generally lose both copies of tumor suppressor
genes to promote cancer.
Ashok
[13:31]
It's been found recently that genes like BRCA2, which my lab has worked on for
a number of years, when you lose both copies, changes happen in cells that make
them particularly vulnerable to certain forms of DNA damage,
and certain targeted agents can induce this form of DNA damage,
and they are extremely successful in treating people with cancers that lack
the activity of BRCA2 and other related genes.
So these are the three conceptual examples, and I think they reflect a lot of progress.
We're rapidly developing new modalities as well, from small molecule drugs and
antibodies to new types of compounds that degrade targets, so-called degrons, protax, for example,
as well as the potential for therapeutic RNA and RNA vaccines for cancer,
which have really Really, there's been a lot of focus on these types of approaches
following the COVID epidemic,
which really accelerated progress in the field, and these are new emerging modalities
to reactivate the immune system against cancer.
[14:43]
Immune System Activation in Cancer Therapy
Ashok
[14:44]
That reminds me that I forgot one really, really important event,
which, in fact, partly happened at Berkeley, not far from you.
Ashok
[14:54]
And that is the discovery that, contrary to our previous thought,
that cancers do activate the immune system.
It was previously thought that they don't activate the immune system much,
and they just grow because they are so similar to our normal cells.
But in fact, it's become clear that cancers do activate the immune system,
but the way they grow is by invoking mechanisms that suppress or evade the immune response.
Ashok
[15:24]
And the discovery by Jim Allison, who was previously at Berkeley and started this work there.
In fact, he was one of the people trying to recruit me at that time to Berkeley.
And Jim later moved to New York. He's now at the MD Anderson.
But his work and that of Tasuku Honjo in Kyoto and Tokyo in Japan showed that
you could reactivate the immune system, the sleeping immune response against cancers.
And this has proven to be an extremely successful mode of cancer therapy,
and it's really exciting. So, I should really have added that as the fourth
major concept in cancer therapy.
But what I said about the newer modalities like cancer vaccines,
[16:07]
Effects of Untreated Cancer
Ashok
[16:06]
RNA therapeutics, etc. still holds.
Brent
[16:08]
Yeah, that's amazing. And if cancer goes untreated, could you maybe explain
at a high level how it ends up killing us?
Because what's the result of these genetic mutations?
Ashok
[16:20]
So typically the result of the genetic mutations that drive cancer is to cause unbridled.
Ashok
[16:29]
The word neoplasm, in fact, means that, a new growth.
So cancers can kill in many different ways.
One way is simply by pushing against adjacent structures and disrupting our
normal physiology, the ability of our body to function, and thereby inducing
side effects that eventually kill us.
The second way is that cancers can metastasize or spread.
Some cancers are particularly notorious at doing this, for example,
malignant melanomas in the skin.
The primary lesions may be tiny little skin lesions, which look pretty innocuous,
but inside they're spreading all over the place, the liver, the brain, etc.
They take over these tissues, and those side effects eventually kill us.
Cancers can also secrete a lot of factors which can have side effects which are very deleterious.
And some of these factors appear to cause something called cachexia.
Cachexia is essentially a wasting syndrome which is characterized by loss of muscle mass.
Ashok
[17:39]
Patients with advanced cancer, particularly, for example, pancreatic cancer,
they still continue eating. Their calorific intake may be normal,
but they're just wasting from inside.
They become terribly emaciated and weak, and they die from the complications of cachexia.
So these are some of the ways that cancers can kill, either locally,
[18:03]
Metastasis of Skin Cancer
Ashok
[17:59]
during their spread, or by systemic effects like cancer wasting.
Brent
[18:04]
And then during the spread is, so let's look at the skin cancer example.
Are those like skin cells growing in places they shouldn't be growing or are
those taking over and adapting to the new type of tissue?
Ashok
[18:16]
It's another really interesting question, Brent. So, cancer cells represent
but are not faithful mimics of normal differentiation steps typically in their tissues of origin.
So, even if, for example, a melanoma arises from pigment cells in the skin,
it does not really accurately reflect all of the differentiation steps that occur in those cells.
And this is common with cancer cells where they may de-differentiate,
they may differentiate down slightly different lineages, and so on.
Ashok
[18:51]
So when they spread, they tend to spread to particular tissues.
Nobody really understands this fully, but some molecular clues have been emerging
from the work of a number of groups across the world, suggesting why,
for example, prostate cancers particularly have an affinity to metastasize to the bones,
breast cancers metastasize to the liver, the brain, for example.
And so there are many different ways in which cancers have an affinity.
When they arrive in the tissues to which they metastasize, it's pretty clear
that they undergo some changes.
And the reason is that they undergo further genetic variation at the sites that
they grow metastatically compared to the primary tumor, although they still
retain quite a degree of resemblance.
So yes, there is a lot of adaptation.
Ashok
[19:46]
Adaptation probably that initiates the movement out of the local primary site.
Adaptation to enable spread via the blood or the lymphatic vessels.
And finally, adaptation at the site where they seed to enable them to grow there.
It would be a different environment.
[20:04]
Treating Cancer Cachexia
Keller
[20:05]
And then another question about the cachexia, do the effects of that have to
be treated distinct from the cancer itself, or can they be treated within the same protocol?
Ashok
[20:14]
They have to be treated concurrently, but we don't have very good treatments
at the moment, sadly, for cachexia.
In fact, we don't understand the origins of cachexia very well.
Well, there's some recent work suggesting that certain hormonal factors which
are involved in regulating appetite, for example, a factor called GDF-15,
may also be implicated in some way.
An abnormality in the regulation of this factor may also be implicated in cancer cachexia.
But we don't yet, at the moment, despite these breakthroughs,
we don't yet have a really good way to handle cancer cachexia.
A lot of the treatments that we can offer are symptomatic or supportive by parental
nutrition and other approaches.
Brent
[21:01]
Isn't a large issue with that going to be if you were to try to increase growth
in the muscles, you're going to be increasing the growth in the cancer cells with it?
Or if you're trying to kill the cancer cells, you're going to be killing more of the other cells?
Ashok
[21:14]
Interesting question. Question. Normal cell growth, for example,
in muscle is quite different from the sort of uncontrolled growth in cancer cells.
And so it probably is not going to be increasing the risk.
That said, if somebody takes substances like, for example, hormones to bulk
up their muscles, there may be risks that could include cancer or other changes in their tissues.
But just Just normally working out, I would say no fear.
Brent
[21:46]
Yeah, because that's where I was like kind of referencing, it's just like people
who take like growth factor and like those type of things, that could also like
increase the likelihood of like cancer growing.
Ashok
[21:55]
It could, it could. I have to say that the evidence such as there is,
is not very complete, but in theory it certainly could.
Brent
[22:03]
Okay.
Ashok
[22:05]
In fact, certain factors like insulin-associated growth factors have been implicated
more directly, but not sort of the supplements that you're talking about yet.
[22:18]
Genetic Predisposition to Cancer
Keller
[22:18]
I think we've talked a good amount about the relationship between genetics and
cancer. I just want to make sure,
is there anything else regarding predisposition that we should cover?
Are some people predestined to get cancer?
Ashok
[22:31]
I would say that the predestination is really best talked about in terms of risk.
Certainly, people who inherit, fortunately, quite rare genetic mutations that
give them an extremely high risk of cancer are almost predestined to develop
cancer at some point during their lives.
Fortunately, as I said, these types of mutations are rather rare.
So for the vast majority of us, it's less predestination and more a balance
of risk, which, as I spoke about earlier,
is really a combination of many things, including our genetic inheritance and
its interaction with our environment.
I say this because I don't think the two work in isolation.
Ashok
[23:20]
Let me give you an example. For example, we've known for some time that diabetes
type 2, which is the adult form of diabetes,
which is virtually epidemic in Asia, which you may have encountered in your
travels, as well as in countries like the United States and the UK,
the incidence is steadily rising,
is associated with an increased risk in cancers in several tissues,
for example, the breast, the pancreas.
We don't know how or why, but my own thinking is that there may not just be
a genetic and environmental risk of developing diabetes,
but some of the factors that predispose to this risk may also be increasing
the risk of cancer through mechanisms which we are barely beginning to understand.
Some of the ongoing work in my lab is trying to tease out some of these factors
using the very powerful experimental system we have to our hand,
[24:26]
Genetic Interplay with Environmental Factors
Ashok
[24:19]
which is the high risk already conferred by BRCA2 mutations in developing cancer.
And our reasonably good understanding of the molecular mechanisms by which loss of BRCA2.
Ashok
[24:35]
Actually causes cells to become cancerous. So using that as a starting point,
we're beginning to ask, can we now begin to explore environmental influences
on increasing or modifying cancer risk in these already high-risk patients?
So a few years ago, we found something quite interesting. I should emphasize
it's still very much in the lab, not yet.
We don't know whether it works in real life, so to speak.
But we found that certain metabolic compounds, which are everywhere,
they are reactive dicarbonyl or carbonyl compounds called aldehydes.
These are generated endogestly in our cells by cellular metabolism.
We're also exposed to them in the environment all over the place.
What we found is that in cellular models of BRCA2 deficiency, efficiency,
cells which carry just one mutant and one wild-type normal copy of BLCA2 were
very sensitive to the effects of these aldehydes in triggering genomic instability,
which we know is a precursor to the development of cancer.
So that's just one small example from my own experience of how our genetic inheritance
[25:59]
Impact of Aldehydes on Cancer Risk
Ashok
[25:53]
could really intersect with our environmental influences to determine risks of cancer.
Brent
[26:00]
And what would be some of the sources of those aldehydes?
Ashok
[26:03]
You know, Brent, when I published this work, I was still in Cambridge.
I don't know whether you know the tabloid newspaper called The Sun.
Brent
[26:11]
I don't think I read it.
Ashok
[26:12]
All I can tell you is its circulation is in the millions.
And I got called up the day our paper was published by a very charming young
lady who said that she was the science correspondent of The Sun.
I didn't know that they even had a science correspondent.
She asked me a number of questions about our work, particularly about where
do the aldehydes come from.
The answer is they are pretty pervasive because they're generated in virtually
every cell through multiple metabolic pathways.
In the environment, for example, the wood glue that holds much of our furniture
together has aldehydes.
Cosmetics contain aldehydes. Car exhaust fumes are a source of aldehydes.
Fortunately, they're rather reactive and therefore short-lived.
So, you know, they switch off equally quickly.
Anyway, the punchline for my story is the next day we had a headline,
by far my highest impact publication ever, In the Sun, saying Cambridge boffins
say booze, shampoo, and many other factors may cause a risk of cancer.
That was their take on our paper.
[27:23]
Natural vs. Synthetic Cancer Risks
Brent
[27:24]
But overall, naturally occurring items have less risk of these things?
It's more like the synthetics?
Or is it even too hard to say that?
Ashok
[27:33]
It's hard to say. There are clearly compounds abundant in nature which can be
potentially pro-casinogenic.
A good example are the toxins made by fungi which live, for example, on moldy peanuts. nuts.
These are pretty potent inducers of liver cancer.
Ashok
[27:56]
Aflatoxins, they're called their whole group, and that's why we have to test
for them everywhere. And those are naturally occurring compounds,
just come from mold or spoilage of food.
Aldehydes are another example. Most of them are generated within us,
but they do occur synthetically.
It's an issue which I think we have not yet got to grips with.
For example, the European Union has been examining the potential carcinogenicity
of literally thousands of chemicals that have been released in our environment
with the growth particularly of petrochemicals,
plastics, etc. They're everywhere.
And they do release compounds into our environment which can affect the risk
of cancer, either directly causing DNA damage or indirectly,
for example, stimulating estrogenic signaling in women, for example.
So, needless to say, although the International Agency for Research on Cancer
and many other bodies publish papers,
periodic reports on cosmogenicity of compounds.
The list of things we encounter in our environment, particularly in the last
40 to 50 years, has grown so high, it's exponential.
We don't know what many of these compounds can do, particularly after longer-term exposures.
[29:15]
Exploring BRCA and Chromosome Custodian
Brent
[29:15]
Yeah.
Keller
[29:15]
And going back to genetic mutations,
is there anything within BRCA that we should cover a little bit more.
And with that, could you give a brief definition of the chromosome custodian aspect of that?
Ashok
[29:27]
Sure. The chromosome custodian aspect, I should say, was a phrase I coined when
I was invited to write a review in Science Magazine about 10 years ago,
which happened to be the 20th anniversary of the discovery of these genes.
And my lab had been one of the first, as I I said, to begin to work on their function.
Ashok
[29:48]
So, the idea that's grown from the work of many labs, including my own,
is that the two breast cancer genes,
BRCA1 and BRCA2, function in many processes that help to safeguard the integrity
of the information carried in our DNA, in our genomes.
They don't work in just one mechanism or one biological process, they seem to cover many.
And in those processes, they seem to work by serving as a focus for the assembly of other proteins,
protein complexes around them, which together constitute little machines that
do jobs like repairing DNA,
resecting DNA, and so on and so forth.
So, the idea of chromosome custodian is simply to catch or enunciate their central
yet quite diverse functions in preserving the integrity of chromosomal DNA in
our genomes. But that's what they do.
I think the only other thing to add is, although BLCA1 and BLCA2 sound very
similar, and they do have common functions, they're very, very different proteins.
So beware, what one does is not what the other does necessarily.
Brent
[31:11]
Okay. And so their proteins are not part of the DNA? No.
Ashok
[31:16]
So the genes, BRCA1 and BRCA2 encode very big proteins.
And these proteins are what actually function in the ways that I said.
Keller
[31:27]
And are we able to test for those mutations?
Ashok
[31:30]
Indeed we are, and we have been for many years.
Genetic testing for people who come to familial cancer clinics,
where, for example, there is a history of many individuals in the same family,
developing, for example, breast and ovarian cancer in the case of the breast cancer genes.
They're immediately offered testing in most countries in the world.
And this can pinpoint whether or not they have what are called pathogenic or
likely deleterious mutations in BLCA1 and BLCA2.
Even that story is not fully done yet and the reason is that there are many,
many mutations that are constantly coming up.
Many of them can be clearly assigned as pathogenic or benign,
but many others are still uncertain.
Their effects are uncertain, still to be determined.
We don't know why there are so many hundreds of these mutations in these two
particular genes in humans across the world, but there are, and the classification is still ongoing.
[32:36]
Gene Editing for Mutation Correction
Brent
[32:36]
And will we be able to use gene editing technology to take or to replace those mutations?
Ashok
[32:44]
That would be a dream. In the case of BRCA1, for example, people who inherit
BRCA1 mutations are predominantly predisposed to cancers of the ovary.
A little bit in other tissues, but not much. One of the problems with BRCA2
or challenges with BRCA2 is that BRCA2 mutant individuals can develop cancers
of the breast, the ovary, the pancreas, the prostate, and many other tissues.
The prospect of gene editing obviously is possible,
but for genes like this, assuming, and we don't know this, that the process
of cosnogenesis proceeds in small steps over a long, long time,
the question would be when can we correct the defect?
Would it have to be in utero before a baby is even born?
Could it wait till people are adult and then you could target particular tissues?
So I think these are some of the challenges.
For myself, I feel if we We understood better the clinical course of disease
predisposition in mutation carriers,
and we found ways to eliminate cells in these carriers which are well on the
road to becoming malignant long before these patients develop cancer.
That may be more tractable, at least in the medium term.
Keller
[34:13]
So do we have any insight to that? We're working with the clinical aspect in
terms of the timing of prevention.
Have you, within your research, been able to figure out when those time slots
that might be best viable are?
Ashok
[34:26]
That's a great question. And let me give you a little bit of detail here in
order to explain my answer.
So as I said earlier, if you inherit one mutant faulty copy of BRCA2 or BRCA1,
you have a high risk of developing cancer.
But often, particularly with BRCA1, cancer doesn't really start progressing
until you lose the second copy in the same cell.
Ashok
[34:56]
So there are clearly turning points like that, which are essential steps in
the road to malignancy in mutation carriers.
We know some of them, we don't know all of them.
So there are many projects now underway. Some of them are funded by the Gray
Foundation in New York and others funded by the National Institutes of Health
as well as other bodies across the world which are trying to create what are
called pre-cancer atlases,
from non-malignant tissues of patients who carry some of these cancer-predisposing
mutations to try to understand what is the roadmap of events that lead these
normal but somehow flawed cells carrying the mutation all the way along the road to cancer.
And when these maps are complete or more complete, I think we will better understand
how and where we can intervene.
Keller
[35:57]
And is there any idea on how the individual monitoring would work?
I understand the roadmap at a broad level, but for the individual impacted, is there any?
Ashok
[36:05]
So already many, but not all, patients carrying BRCA1 or BRCA2 mutations will
notice that there's a high familial occurrence of cancer.
They will present at familial cancer clinics or themselves, sadly,
be diagnosed with cancer, and the family history will come out when they're
being diagnosed and treated.
So, patients at high risk can be identified through the genetic testing that
I said, and if they are identified, then one can monitor them.
So, in BLCA1, BLCA2 mutation carriers, you can monitor for breast cancer risk,
often by self-examination or by imaging periodically.
You can monitor for ovarian cancer risk through blood tests or through imaging.
And you can offer patients, if they do show signs that malignancy is imminent
or even in a pre-malignant setting, approaches to decrease the risk.
For example, Angelina Jolie, the actress whose family inherits the BSA1 mutation,
opted to undergo pre-cancer operations to remove tissues like breast tissue,
ovarian tissue, that were at risk of developing cancer.
Brent
[37:22]
What would some of those pre-malignant symptoms be?
Ashok
[37:25]
There may not necessarily be symptoms at the very earliest stages,
but you might notice a lump, or you might notice something abnormal in imaging,
which is obviously much more sensitive to very small changes.
But there are developments afoot across
this field and it's very exciting that many researchers
are now identifying not just in BRCA1 or
BRCA2 mutation carriers but in people
who have no apparent predisposition to cancer
that there is circulating DNA which carries some of the abnormalities present
in cancer cells which has probably been released into our circulation population
from very small numbers of these cancer cells which haven't yet reached the
point where they're causing symptoms or they're even detectable.
So these blood tests are on the increase. They're being offered everywhere right
now, mainly to high-risk groups, but hopefully eventually to anyone after a certain age perhaps.
And they should be able to tell us whether there is a high index of suspicion for cancer.
They may not tell us that there is cancer or where that at cancer risk,
but they should be able to say, this person has a strong likelihood of cancer.
And typically, these blood tests will need to be followed up by more specific
tests, perhaps imaging.
[38:47]
Focus on Prevention Over Treatment
Ashok
[38:48]
So, there is the prospect of early detection and eventually early therapy or
potentially even prevention of cancer, which has been what I've been working
on, the reason I've worked on BRCA1 and BRCA2 for the last 25 years.
In fact, in the Medical Research Council Cancer Unit that I used to direct for 15 years in Cambridge,
we started off from the early to mid-2000s focusing on prevention rather than
treatment of the advanced disease because there was so little research at that
time being carried out in this area,
although it was pretty evident that if you catch cancer early,
the clinical outcomes are so much better than for treating advanced cancer.
Brent
[39:31]
So let's dive in a bit more on what are the best steps for prevention?
Do you see the future of genetic testing becoming cheaper, easier,
more accessible, helping that?
Do you see just healthy lifestyles? Where do you want people to focus? this.
Ashok
[39:45]
So I'm a great believer in so-called 4P medicine, which Lee Hood and others
have been promulgating for many years now.
And I do think that with our increasing genetic understanding of cancer,
it may be one of the diseases which is first to cross some of the boundaries,
if you will, for the ideal dream of 4P medicine.
So, already, cancer therapy is becoming highly personalized. Why?
Because when you get cancer, each of the types of cancer that people get have
different mutations, and increasingly, we're developing therapies that can help
to target those cancers.
Ashok
[40:30]
The issue of participatory medicine, I think, has always been the case with cancer.
People have to be involved in their care because these are sometimes pretty
serious therapies, so patients have always been very much involved in care.
In terms of predictive and preventive is where our biggest challenges lie.
As I was describing, it's extremely heartening to see that there are emerging
quite generalized tests out there which could say someone is at risk of developing cancer,
even if they don't have a genetic predisposition, even if they don't have an
obvious risk factor like smoking 10 packs of cigarettes a day.
Ashok
[41:17]
And that does happen in this day and age, unfortunately. So the point is,
can we move towards that type of testing?
In my ideal world, yes, but there are many caveats, some of which I'll allude to now.
Ashok
[41:37]
First, this is an expensive business. If someone has a blood test which indicates
high index of suspicion, they have to undergo usually imaging tests,
like magnetic resonance imaging or other expensive modalities,
which are not just expensive, they're often inaccessible.
And that brings me to the second point.
Even in developed countries like the United States, there is an enormous disparity
in access to cutting-edge health care, including preventive care if it involves
expensive imaging of this kind.
Let alone in the rest of the world, the disease burden in the poorer countries,
the low- and middle-income countries in Asia,
is extremely limited, and so people often present with diseases like cancer
at a far more advanced stage than they would in the United States or in the UK.
Okay, these are socioeconomic challenges.
The science is running ahead, but the sad fact is we're not able to offer the
benefits of those scientific advances to all the people who really need and deserve them.
And this, to my mind, is a great tragedy. I don't have a solution,
so I'm highlighting something that I see as an issue that the world has to contend with.
I don't think we can live in our silos as science runs ahead. head.
Ashok
[43:01]
The second set of issues is, okay, so you find that somebody has a high index
of suspicion of cancer, you do your imaging, and you find, yes, there is a small growth.
Sometimes it's possible to surgically resect or remove that growth,
again, a fairly expensive form of medical care,
but we don't yet have safe and effective drugs that could be used to treat those
patients for the medium to long term to eliminate early cancers or to prevent them from developing.
And the challenges to developing those sorts of therapies are also high.
Unlike conventional cancer therapies where patients could be dying unless you
treat them, these are essentially healthy and potentially asymptomatic individuals
who have some evidence of an early growth.
So, any drug that you administer to them ethically has to be extremely safe.
They may need to be on this drug even periodically for long,
long periods, so the drug has to have low long-term toxicity and high long-term safety.
Ashok
[44:14]
And last but not least, we need to find less expensive ways of monitoring patients
so that if we are subjecting them to this form of preventive care,
we actually know what's going on.
And all of these challenges have made the drug industry, big pharma companies, for example,
extremely reluctant, in my opinion, to invest in the development of therapies
that would be purely preventive because of the difficulties and challenges in
testing their efficacy, testing their safety before they can be administered.
Brent
[44:49]
Are people looking towards certain natural medicines for some of these longer-term ones?
Because I know there's been conversations around certain mushrooms being anti-cancerous.
And so, what are some of those possible routes?
[45:09]
Potential of Natural Medicines
Ashok
[45:05]
Sure. There's a lot of discussion about natural medicines.
I'm not an expert in the field, so please take whatever I say with a huge pinch of salt.
It is pretty clear that traditional pharmacopoeias or lists of drugs that traditional
medicine, particularly in Asia, has developed, Chinese and Indian medicine,
has yielded some valuable pharmacologic agents which have been and purified
and have shown to be really effective.
I still remember there was an Indian herb that I learned about when I was training
that turned out to contain a very potent antihypertensive, which was later purified and used.
And there are many examples, including the anti-malarial drugs that have recently
been developed from Chinese herbs.
So yes, there are lots of compounds naturally occurring in mushrooms,
other plants, for example, with such activity.
Ashok
[46:02]
And the good thing is that many of them have a track record of safe administration
at certain doses for long periods of time.
So, there is potential there. The problem, though, is in conducting convincing
statistically robust trials which show benefit,
and to my mind, these trials in cancer prevention are rare or non-existent,
and therefore a lot of the evidence
and the discussion is again wearing my scientist hat, somewhat anecdotal,
so I think there's a lot of potential work to be done in this area.
It's all very interesting, but I think the scientific evidence base is rather sparse.
Brent
[46:45]
Do you think part of the issue is funding those trials because you can't patent
the discovery of a plant?
Ashok
[46:53]
It could be patenting. The other reasons for funding is the long-term nature
of these trials, variable activities in natural medicine preparation.
So if you don't know what the active ingredient is, how do you know if an herb
preparation made on one day has the same activity as something made a month later?
There are many, many challenges.
It is pretty clear, as I alluded to earlier, that naturally, perhaps,
pharma wants to recoup its investment into research and development within a
reasonable period, and currently patents, when they're granted,
run for a period of about 25 years.
So there's a lot of focus on the market potential of investments into new medicines,
and in that category, I think you're absolutely right, preventive drugs,
natural herbal medicines,
are not high profile because the potential market returns for all the reasons
I've said and that you mentioned are relatively low.
I think these are issues we need to begin to think about because otherwise how
are we ever going to reach this goal of 4P medicine?
Keller
[48:06]
Do you think the need for, you know, going into market affects the innovation broadly?
Like, do people, I guess with that, do you feel like there's differences within
funding agencies, whether it be philanthropic, you know, private or, you know, state funded?
Do people have different levels of innovation with which they're approaching cancer?
Brent
[48:26]
And then also maybe, have you seen a difference between like Asia and the UK
and where you've worked?
Ashok
[48:31]
Sure. Let me try and comment. There are a number of complicated issues,
so you'll forgive me, please, for simplifying some of the points here.
[48:41]
Innovation Disparities in Cancer Research
Ashok
[48:39]
So let me try and take them as directly as I hear them.
First, are there differences in the level of innovation being brought to bear?
Let me put it as even the level of effort being brought to bear,
for example, on advanced cancer therapy with clearer market potential than preventive
research or research into to potential drugs or compounds or natural substances
that could delay or prevent the onset of cancer? My belief is yes.
There is a lot more funding available still for research in cancer therapy than
there is on understanding the causes of cancer and how they can be translated
to cancer prevention. mention.
Second, you asked about whether there is a pulling effect of pharma market potential on research.
I believe that there is. I've witnessed in Europe and the United States that
many academics are involved in startups, consultancies, interactions with industry.
And I think at the moment, at least, industry's natural focus has to be on things
where they can and recoup investment into research and development,
and clearly, at least for the time being, research into cancer.
Ashok
[49:56]
Provides a more direct route to achieving that than the other issues that we have talked about.
And so I believe, yes, there is a pull effect as well.
Finally, is there a difference between Asia and the UK where I used to work?
Yes, I do see some differences. For example, there is quite a lot of investment
that I see into traditional Chinese medicines here in Singapore,
particularly particularly in China, that I'm witnessing after moving to Asia.
Ashok
[50:26]
How high that level of investment is compared to investment in more conventional
approaches, I can't really say. I don't know.
But it does remind me to make an important point, which is another point I should
have explored earlier, but I'll make it now.
About half of the world's population is in Asia.
80 to 90 percent of studies in cancer have been carried out in people of European
descent in Europe or the United States.
It's pretty clear that the types of cancer we see in Asia may not be exactly
identical to the types we see in the UK and the US.
For example, there are some forms of cancer, nasopharyngeal carcinoma,
which appear to be uniquely prevalent in East Asia.
There are other forms of cancer which are relatively uncommon in the US and
in Europe, which are much more prevalent here.
For example, certain forms of breast cancer, certain forms of ovarian cancer,
certain forms of lung cancer.
So it's clear that our genetic inheritance, which is clearly different between
Asian populations and European populations, does affect Genesis.
Ashok
[51:42]
The progression, and the therapy of cancer. And I feel these issues are somewhat
under-researched in the Asian population,
despite it representing over 50% and perhaps more in the future of the world.
That's one of the factors that brought me here from the UK to Asia.
I think there are so many things to do here in this really wonderful,
exciting environment in Singapore poor where things as you've witnessed in your
time here happened so fast.
Brent
[52:14]
Yeah my sister is a genetic counselor in
chicago and she works with a predominantly underprivileged like neighborhood
area and she gets i think there was a recent update on like their data set and
the predisposition for one type of cancer just skyrocketed and they're like
like that's how quickly that her field is changing because they're just now
starting to address some of those like disparities exactly Exactly.
Ashok
[52:36]
I mean, some of the disparities even occur between Asian Americans,
African Americans, for example.
And it's difficult to study those, particularly the really small minority populations
in the context of the much larger European populations in the United States.
So I think Asia has a lot to contribute, which may have an impact in countries
to which Asians, for example, have migrated, including the United States.
Brent
[53:01]
Yeah, I can also see definitely a huge difference in some of the epigenetic
results of air pollutions and different practices and ways of living that are
completely different here than they would ever be in Europe and the US.
Ashok
[53:13]
No question. And this is part of the very enjoyable culture shock that I've
been having over the last two years of living in Singapore.
I'm enjoying every minute of it, and I find it rather an exciting research scene,
but but also a place from which I'm beginning to explore Indochina,
which has so far been a bit of a black box as far as my knowledge of culture
and history is concerned.
Brent
[53:36]
Yeah, I've definitely learned a lot being here too.
Keller
[53:38]
Absolutely. Research on traditional Chinese medicine only being done in China,
have you seen other areas?
Ashok
[53:44]
Certainly being done in Singapore as well that I've seen, yes.
So it's not just in China. Clearly China has a large focus on this.
In fact, there are several companies that are trying to produce drugs,
even in the United States, based on traditional Chinese medicines.
So, China is very active in this area.
[54:05]
Traditional Chinese Medicines in Research
Keller
[54:03]
It's super interesting. We haven't, like, obviously gone from back home.
We never got to see that, but all the different areas and the shops and the
variety of supposed treatment options has been really interesting.
Ashok
[54:12]
It is amazing, isn't it? And it's very manifest in Singapore because there are
reasonable regulatory controls.
I don't know China very well, so I don't know how well they're enforced there.
But clearly a lot of belief in and access to traditional Chinese medicine.
So yeah, very interesting.
[54:31]
Generation to End Cancer Hope
Brent
[54:32]
And would you say we are going to be the generation to end cancer?
Ashok
[54:37]
I really hope so. It won't be my generation. I think it'll be yours.
Um, there is so much that is closer than ever when I certainly from when I started
working on this problem,
still, there are goals, particularly in the area of early intervention in cancer,
cancer prevention that still seem a long way away.
So, I do hope that your generation will see, if not the end of cancer,
a significant amelioration in its impact on our lives.
Believe it or not, it's estimated that somewhere between one in three to one
in two of us is going to suffer from cancer at some point in our lives.
Brent
[55:17]
Wow. And do you have any general advice for people to how to best avoid getting
cancer, whether or not they know they're genetically predisposed?
Ashok
[55:27]
I don't really, Brent. All I can do is to give very general advice,
which I think most of which is common sense.
Stay healthy, be moderate, do the usual things to enjoy an active and healthy lifestyle.
That's about as much as I can say, apart from avoiding things like,
for example, cigarette smoking, which clearly elevate your risk of cancer.
Keller
[55:53]
And then do you have any advice broadly to students interested in studying cancer
or the particular areas within the research that you think needs more focus?
Any recommendations of things that helped get you to where you are?
[56:06]
Advice for Students in Cancer Research
Ashok
[56:06]
Let me again try and break that down a
little bit Keller First is my advice to
any student Thinking about entering the broad area of cancer research Just two
words Do it Do it now It's really exciting We're on the cusp of so many breakthroughs
And you could be a part of these transformative events In the near to mid-term future.
Ashok
[56:34]
What are the areas that personally I find really interesting?
There are several of them. It'll be no surprise from the focus and thrust of
my work for many years now,
I'm really interested in the intersection between our genetic inheritance and
environmental factors in making each of us more predisposed or susceptible to cancer.
I'd like to understand how this works. I'd like to understand how these factors
influence the earlier steps in the origins of cancer and with that information
I would like to be able to prevent or at least delay the onset of cancer in everybody.
Ashok
[57:13]
There are so many scientific challenges.
They're multidisciplinary challenges they involve the requirement for people
with knowledge of handling big data and populations on genomes or mathematically
inclined people they involve,
people with interests in molecular cell biology.
They will include people with interests in engineering, engineering devices,
for example, that may help us to pick up early signs of disease.
So there are many, many things that really need to be addressed.
May I just stop and switch that off?
Brent
[58:13]
It's my partner.
Ashok
[58:17]
So let me break for a moment and just resume so I think that's one area that
I find really exciting and in need of people from all sorts of different disciplines
Other areas include, for example,
the still not very well understood influence of the immune system on the origins
of cancer and how we can actually use it,
exploit immune reactivity to treat or potentially prevent cancer.
So, for example, as I mentioned earlier, cancer vaccines, treatment of cancer,
as well as preventive vaccines.
These are two of the many, many areas that I think deserve attention.
I could go on for the next hour, but I won't.
Brent
[59:05]
Perfect. Well, thank you so much for coming on today. It's been great.
Ashok
[59:09]
It's a real pleasure. I hope that my remarks will prove useful and interesting
to at least a few people on your campus and perhaps in NUS. Thanks again for having me on the show.
I really enjoyed all your penetrating and very interesting questions. Thank you very much.
Keller
[59:24]
Thank you.