Five ways scientists are winning the cancer arms race
Joyce Dall'Acqua Peterson and Mark Wanner
In this article, we examine the different ways cancer escalates the conflicts within our bodies, and how scientists are leveraging the incredible power of genetics and genomics to disarm it.
For most of human history, cancer was considered a monolithic enemy — a mass that grew and eventually spread to vital organs such as the lungs or brain, eventually killing the patient. Weapons of mass destruction were directed against this enemy: surgery (accounts go back to antiquity), radiation since the early 1900s, and chemotherapy since around 1940. Some patients shorthand these unpleasant options as “slash, burn and poison.”
The so-called war on cancer, initiated with the National Cancer Act of 1971, didn’t wipe out cancer, but it did launch an era of much better profiling of the enemy. Cancer, it turned out, is not one disease but many, and cancers are best characterized not by location in the body but by mechanisms (such as the close links between breast and ovarian cancers).
Today’s search for cancer cures is more closely related to hunting down cyber-criminals than conducting a pitched battle in a theater of war. Just as cyber-criminals use tricks of digital code to defraud and delude their victims, cancers manipulate genetic code to wreak havoc on the body through a variety of mechanisms. These include hijacking the body’s immune system, activating invasion and metastasis, and turning off normal growth suppressors and cell death.
Read on for five ways JAX scientists are winning the cancer arms race.
JAX Professor Roel Verhaak (right) and members of his cancer research team at JAX Genomic Medicine in Connecticut. Photo by Cloe Poisson.
1. Finding the cancer dangers that are hidden in plain sight
In the hunt for genetic cancer risk factors, researchers painstakingly analyze huge amounts of genome sequence data. They look for specific mutations that increase or decrease susceptibility, as well as larger-scale genomic patterns that may do the same.
Research has led to tests that identify the mutations driving cancer in individual patients as well as treatments that target those specific cancers.
But all along, there have been cancer‑causing genetic anomalies that remained hidden from standard sequencing protocols. One kind is found within the genome itself: structural variants (SVs), including duplications, insertions, deletions and inversions of normal DNA sequences, that are difficult to spot because they don’t change the sequence data. Recent advances in long‑read sequencing are revealing how common SVs are even in healthy people, and they have also been implicated in multiple cancer types.
Now the significance of another cancer danger is coming to light: extra-chromosomal DNA (ecDNA). This DNA somehow becomes separated from the chromosomes themselves and forms a circular structure in the nucleus. Its segments may contain many copies of various genes, adding to the two copies found, as usual, in the chromosomes themselves. And if ecDNA sequences contain cancer-promoting genes, it can cause havoc.
Advanced cancers often have severely disrupted genomes, but the mutation or dysregulation of just a single gene can start cells on the path to malignancy.
A variety of factors can cause cancer-related genes to produce either too much or not enough of a protein. Loss-of-function mutations or deletions of genes such as BRCA1 and BRCA2, which promote the regulation of cell division and DNA repair, and TP53, a tumor suppressor also involved with suppressing cell proliferation, are well-known as cancer risk factors. Other genes, known as oncogenes, become dangerous when they are over-expressed. Oncogenes such as EFGR and Ras produce proteins that promote cell growth, differentiation and proliferation, while myc regulates the expression of many such proliferation-related genes.
When a DNA segment breaks away to form ecDNA, it loses the usual systems that control gene expression. Therefore, ecDNA can be highly transcribed and, if it contains any coding genes, yield an abnormally large amount of protein. When those genes include oncogenes, the normal checks and balances on cell growth and division can be overwhelmed by the uncontrolled protein production, leading to cancer initiation and tumor formation.
Implicated in cancer
It has become increasingly recognized that genomic lesions, which increase oncogene expression, play a role in some cancers, including SVs within chromosomes and ecDNA formation. Researchers first spotted ecDNA in cancer cells decades ago in quite a literal fashion, using fluorescent probes that bound to specific sequences and lit them up, showing that they were physically separate from the typical chromosomal structures in the nucleus. There were still questions surrounding both the prevalence of ecDNA in cancer and the role(s) it might play in disease progression and treatment strategy.
JAX Professor Roel Verhaak, Ph.D.Brain tumors, sequencing, computational biology.Roel Verhaak
has been investigating aspects of ecDNA, particularly in the context of glioblastoma, a brain cancer that is highly resistant to conventional cancer therapies. He found that ecDNA is unevenly inherited by daughter cells during cancer cell divisions, creating important differences between cell populations. It makes sense — while chromosomes are evenly divided in a highly controlled process during cell division, ecDNA has no such regulation and is passed to daughter cells seemingly at random. The differences increase as the cells continue to divide, creating what is known as genomic heterogeneity within the tumor. If there are many sub-populations of cells with different properties, it becomes very difficult to find an effective therapy strategy to eliminate all of them. Therefore, ecDNA not only contributes to glioblastoma initiation, it can also provide a mechanism for therapy resistance and tumor recurrence.
More recently, Verhaak and colleagues took a broader view to assess ecDNA frequency and clinical impact across multiple cancer types in thousands of patients. They found that ecDNA is far more common in a variety of cancers than previously thought — by more than 15-fold— and while its presence is often amplified in cancer cells, it is not in normal tissues. Furthermore, patients whose cancers carry ecDNA with increased oncogene expression have more aggressive cancers than those without. Indeed, ecDNA amplification in tumors was associated with significantly worse five-year survival outcomes.
Is ecDNA a key to stopping therapy-resistant cancers?
The discoveries are a crucial first step toward finding preventions or effective therapies for these dangerous cancers. The insight into ecDNA’s prevalence and importance will fuel exploration into potential clinical targets. For example, how does ecDNA form? Can it somehow be neutralized before it can cause harm? Also, how can diagnosing ecDNA-positive cancers help guide treatment strategies? The findings that ecDNA may underlie some of the most difficult-to-treat cancers indicate that new therapeutic approaches are needed to improve patient prognoses.
While learning that ecDNA increases cancer lethality may be alarming, knowledge is power.
“We are on a mission to improve the outcomes of patients with cancer,” says Verhaak, “and our ecDNA discoveries are pivotal for achieving those goals.”
JAX scientist Gary Ren (left) and colleagues at his Maine-based cancer research laboratory. JAX photo by Tiffany Laufer.
2. Derailing cancer metastasis
'Metastatic cancer is the most dangerous and remains the most lethal.'
As cancer therapies improve and grow ever more precise, many cancers can be eradicated or effectively shut down at their site of origin. While medically serious, these primary tumors usually have growth pathways that are targetable, and there are now many effective treatments available. Nonetheless, there were 9.5 million cancer deaths worldwide in 2018, and that number is expected to jump to 16.4 million by 2040. So why do so many patients still die?
Unfortunately, not all cancer cells are the same, even within the tumor, and not all of them stay put. Some break away from the primary tumor and move to other locations in the body, in a process known as metastasis. Metastatic cancer is the most dangerous and remains the most lethal. Understanding the processes and variables underlying metastatic cancer and how it might be stopped is therefore essential if we are to make the next leap forward in improving cancer care.
How does cancer spread?
When cancer begins, it usually involves a single rogue cell. Somehow the brakes come off the carefully controlled cell division cycle, allowing the cell, and eventually its many descendants, to grow and divide with relentless speed. As it grows, it quickly adapts to and co-opts biological systems within its particular organ or tissue.
At a certain point, however, cancer cells begin to move, either by growing into other tissues or separating from the original tumor. Cells that break away travel through the blood stream and lymph system to other places in the body. These cells face long odds, and most of them are eliminated by the immune system or fail to adapt to the environment in which they settle. Sometimes they escape immune surveillance for long enough, and adapt to their new environment quickly enough, to survive the transition. Eventually—weeks, months or even years later—they begin to thrive once again and grow aggressively, resistant to treatments that may have worked well for the primary tumor.
Cancer researchers are investigating the steps in the metastatic process to look for ways to stop cancer from spreading. Could immune surveillance be enhanced to eliminate cells before they reach other areas of the body? Could the environments in other tissues be made less hospitable to the cells that infiltrate them? And if they’re not eliminated before reaching a destination, is there a way to maintain metastatic cells in a senescent state, keeping them inactive by undermining their ability to grow and divide? If the answer is yes, and a therapy can be developed that prevents metastatic cancer growth, it would save many lives.
When metastatic cancer cells migrate elsewhere in the body, they’re on their own, and have to deal with a new environment and immune cells. So how are they able to succeed in there, so to speak? Ren is investigating the complex interplay between immune cells and cancer cells, and between different kinds of immune cells, that can dictate success or failure of metastatic cancer spread. Of particular interest are cells known as neutrophils, which are part of the innate immune system, the first line of defense against invading pathogens. Recent research in Ren’s laboratory has shown that neutrophils also play surprising roles in cancer metastasis.
Ren and his team worked with specialized mouse models to look at breast cancer cells that migrate to lung tissue, a common site for breast cancer metastatic spread. They are often eliminated by either neutrophils or natural killer (NK) cells, another component of the innate immune system. In an unexpected result, however, Ren found that when both neutrophils and NK cells are present in lung tissue, the neutrophils don’t react against the cancer cells. Instead, they actually inhibit NK activity, helping the metastatic cells survive and increasing the chance of cancer spread. The finding helps to explain why treatments that increase neutrophil counts in cancer patients, which are often greatly reduced by chemotherapies, are associated with higher risk for subsequent metastatic disease.
In addition, the research team discovered that neutrophils in the lung tend to stock up on fuel in the form of lipids when a breast cancer tumor is growing. Interestingly, the process is stimulated by molecular signals sent from the tumor itself, even before its cells begin to migrate elsewhere. Then, when circulating cancer cells do arrive in the lung, the neutrophils transfer the lipid fuel to them, increasing their ability to survive and proliferate.
Targets for treatment
More research is needed into exactly why neutrophils function as both safeguards against metastasis and, in different contexts, as part of the support system for it. Nonetheless, Ren’s findings provide intriguing targets for therapy refinement and development. For example, assessing NK/neutrophil populations can help inform whether or not to increase neutrophil counts following initial therapy. And disrupting the signaling/metabolic cascade that helps fuel metastatic cancer cells in the lung could greatly reduce the chances for successful spread. These and other treatment regimens are both parts of the larger effort to derail cancer spread and, ultimately, deaths from metastatic cancer.
John Pierce is a cancer patient who is participating in the Maine Cancer Genomics Initiative. Pierce was able to take part in the MCGI tumor board meeting online in March. Photo by Alexandra Giardino.
3. Creating a model for personalized cancer care
From cancer genomic testing to clinical trials, John Pierce is exploring the latest advances to address his medical issues.
What advice would John Pierce give to someone who has just received a cancer diagnosis?
"First, be your own best advocate. When I was a 20-year-old combat helicopter pilot in Vietnam, I learned that when someone or something is trying to kill you every day, you recognize that nothing focuses your mind like your own mortality."
Second, he says, "get genomic profiling."
Nearly 50 years after his combat experience, Pierce is now retired from a successful and varied career as an internet consultant. And following a series of unusual health crises that trained him to seek out the best medical advice and treatment, he has been diagnosed with cholangiocarcinoma — a very rare cancer of the bile ducts, the slender tubes that carry the digestive fluid bile through the liver. Pierce is now bringing his lifelong facility for quickly acquiring technical expertise to his treatment regime, to be his own best advocate.
Pierce may not be your average cancer patient, but every patient, and every cancer, is genomically unique. Pierce says that when he learned he had cancer, “my first inclination was to obtain genomic testing. Cancer isn’t liver cancer or lung cancer; it’s defined by whatever the cancer’s genomic profile is. And that’s why I started down this path and requested testing.”
Pierce’s oncologist is Dr. Roger Inhorn of MaineHealth, a steering committee member of the Maine Cancer Genomics Initiative (MCGI). JAX founded MCGI in 2016 with a grant from the Harold Alfond™ Foundation and has enrolled every oncology practice in Maine and most of its oncologists. In phase one of the program, which concluded at the end of 2020, participating oncologists submitted patient tumor samples to be sequenced and profiled for genes known to be associated with various cancers, and with response or resistance to approved targeted therapies or new drugs in development approved by the U.S. Food and Drug Administration.
“For almost all of my patients who have an advanced malignancy and have enough tissue available,” Inhorn says, “I offered participation in MCGI. Genomic profile testing helps clarify potential options by looking for targetable mutations for which there might be either a clinical trial option or a commercially available drug that can be used to treat their malignancy.”
Inhorn notes that like many patients participating in MCGI, Pierce “understands that there is also an altruistic piece to this. They understand that MCGI and the clinical community are trying to learn and create a larger database of treatment options and to engage and educate oncologists about how to best use these platforms. I think the day is coming where everyone who has an advanced malignancy will be offered genomic profiling — it’s going to become a standard of care.”
Tumor profiles from MCGI testing, and their best treatment options, are reviewed at Genomic Tumor Board (GTB) sessions, virtual conferences that link clinicians with experts in cancer genomics and clinical trials. Inhorn mentioned to Pierce that there was a tumor board meeting coming up, and Pierce said, “I’d like to participate. I’d like to be in the room when they’re discussing my case.”
Dr. Jens Rueter, chief medical officer at JAX, says that Pierce’s participation in the tumor board “worked out really well. Beforehand I was a little bit nervous about it because I didn’t really know what to expect. He’s an unusual individual because he embraces new technologies, and that’s coupled with really wanting to impact his treatment plan dramatically.”
Rueter says GTBs are an important component of MCGI, as they often provide the most significant input to clinicians with respect to applying the genomic information in their patients’ care plan. Typically, four cases are discussed during each one‑hour meeting. A brief case presentation by the treating oncologist is followed by a presentation of the genomic case information. Then, external advisors specializing in precision oncology give their interpretation of the case and provide significant guidance to the oncologist and the medical team. In this case Pierce himself was also able to query the experts.
Genomic testing identified two targetable mutations in Pierce’s cancer. He is now on his second targeted therapy (erlotinib) after four months on the IDH2 inhibitor enasidenib.
According to Rueter, most cancer patients fall into one of two categories. “The first are comfortable doing what their doctor says, maybe asking questions or even questioning some decisions, but basically trusting the doctor. And the second tend to shop around for doctors until they find the one who tells them what they want to hear.” Pierce is in a rare third category, Rueter says. “He just wants to know everything that could possibly be done to address his cancer.”
Pierce is continuing to actively advocate for his health. “I think cancer and oncology clinicians today don’t talk about cures; they talk about control. And as far as I’m concerned, control isn’t really good enough for what I’m looking for. I am looking for a cure.”
A model for personalized cancer care in a rural setting
MCGI is a statewide collaboration of JAX scientists and community oncologists that brings innovative cancer genomic testing, education and drug access infrastructure to Maine. Every oncology practice in the state is a partner in the program. Initially driven by the need for greater availability of cancer genomic testing in Maine, MCGI has become a model for community precision oncology, or personalized cancer care, in a rural setting. Precision oncology uses analysis of a patient’s normal genetics and the specific mutations found in his or her tumors to guide more targeted treatments.
“Over the last four years, we’ve made great progress with precision medicine in Maine, especially in rural areas of the state,” said Rueter. “In the first phase of the initiative, we provided genomic tests to over 1,600 cancer patients, affecting patient lives from Caribou to Kittery. Over the next five years, we will focus our efforts on helping patients navigate the steps of entering genome-informed clinical trials and of accessing targeted therapies as part of their routine medical care.”
The initiative also plans to expand its reach to other areas of the northeast United States beyond Maine.
4. Harnessing our immune systems to attack cancer
Our ability to understand and manipulate cancer cells — as well as suppress and kill them — will continue to accelerate over the coming years, so we may be poised at the brink of an important leap forward for effective cancer treatments.
Cancer immunotherapy has become a
hot medical topic over the last decade.
While much remains to be learned, there
have been startling early successes,
and there is exciting potential for
many more in the years ahead.
Like in so many medical
stories, however, it took
many years of research to
figure out how to help our
own immune systems detect
and fight tumors. And the work
began with a discovery in a mouse.
to treat cancer
In 1996, the journal Science published
a paper with an interesting finding.
In mice, blocking a protein that acts
as an immune “checkpoint” resulted
in the elimination of cancer cells,
and even established tumors, by
the immune system. The protein,
protein 4 (CTLA4), normally acts to
suppress the immune system. That may
sound strange, but checkpoint proteins
such as CTLA4 are important parts of
the vital system of checks and balances
needed to prevent overactivation
and toxic immune responses.
Unfortunately, cancer cells use these
checkpoint proteins to evade attack,
flying under the immune surveillance
radar to grow and thrive. Researchers
strove to learn how to put these cells
back on the radar again, whether
through targeting a protein unique
to the cancer cells themselves or by
tweaking immune system function.
The finding in the Science paper
suggested that a new form of therapy
could perhaps be developed by removing
the checkpoint “brakes” on the
immune response in human patients.
Over the past 24 years, it has become
clear that cancer immunotherapy is a
powerful new option for oncologists
and many of their patients. The effects
of the new therapies, most of which are
known as immune checkpoint blockades,
are inconsistent, but when they
work, the results can be surprisingly
good. As a result, the Science paper’s
senior author, James Allison, has become renowned as a pioneer
in the immunotherapy field, the
subject of acclaimed documentary
film “Breakthrough” and was
awarded a Nobel Prize in 2018.
Finding a better checkpoint
Clinical trials for antibodies that
bind to CTLA4 began in 2000, and
by 2010, the first U.S. Food and Drug
ipilimumab (marketed as Yervoy)
emerged. Unfortunately, the overall
survival benefit was, on average, poor.
There were also incidences of severe
immune toxicity, when the immune
system became overactive and attacked
normal tissues as well as tumor cells.
In the meantime, another checkpoint
protein, programmed cell death
protein 1 (PD1), came to the fore.
First discovered in mice in 1992, PD1’s
biological mechanism attracted attention
over the following decade. CTLA4
inhibits immune cell activation early,
in the lymph system, so blocking its
function can lead to large-scale, systemic
immune activity. PD1, on the other hand,
inhibits activity in the peripheral tissues,
including tumor microenvironments.
Without it the immune activation is more
limited and more focused on the tumor area
itself. Much of the preclinical focus therefore
shifted to PD1 inhibition, and in 2014 the
anti-PD1 antibody pembrolizumab (Keytruda)
received FDA approval.
Pembrolizumab has been used to treat cancers
that previously had no effective therapies,
including metastatic cancer and inoperable
tumors. But the majority of patients don’t
respond, and severe inflammation is an
uncommon but potentially dangerous side
effect. So why is there such variability in
patient response, how can the percentages
be improved and how can side effects be
minimized? Research is ongoing into these and
many other questions as scientists and doctors
seek to bring more precision and efficacy to
the cancer immunotherapy field.
Returning to the lab
to improve therapies
Although there are approved
immunotherapies already in
regular clinical use, many researchers
are taking a step back to figure out how to
improve them. Not surprisingly, modeling the
intricate interplay and signaling between the
immune system components themselves and
learning how they interact with cancer cells
is a key part of JAX’s cancer immunotherapy
research program. Leading the effort is Dr. Karolina Palucka, a former
clinician who transitioned to research so that
she could help improve patient prognoses. And
while Palucka is a human immunologist, she
is using mice as the foundation for her work
to identify how to harness the power of the
immune system to prevent and treat cancer.
Experimental mouse models that recreate
human immune response mechanisms have
become an important resource for immunology
research. However, the first generation of
these mice didn’t capture the full repertoire
of immune cell types and functions, including
macrophages and natural killer cells that play
critical roles in cancer initiation and immune
evasion. Palucka is therefore working to
develop mice with an even more complete
human cell population to better understand
their exact roles in cancer cell viability,
growth and potential metastatic spread.
In addition, Palucka is pursuing a therapeutic
strategy based on the concept that T cells,
the immune cells that are able to reject
tumors, can function as anti-cancer drugs
when properly armed for the purpose. It’s
possible that anti-cancer reactive T-cell
populations can be expanded via cancer
vaccines, with the potential to greatly enhance
the efficacy of current immunotherapies.
With careful manipulation, it may soon
be possible to safely and reliably tip the
balance of T-cell function in favor of its
cancer-destroying abilities. It’s an exciting
thought, and one that will drive the cancer
immunotherapy field even further forward.
5. Taking aim at breast cancer
Sophisticated genomic studies are revealing the mechanisms of tumor formation, pointing the way to new targeted treatment approaches.
When a woman receives a diagnosis of breast cancer, how will it affect her ability to continue her career, take care of her children, celebrate her 50th wedding anniversary? The answer will be as singular as the woman herself.
That’s because her cancer has a distinctive
genetic profile. Researchers have discovered
dozens of genetic variants associated
with breast cancers, and are racing to
develop targeted treatments that disarm
the destructive power of cancer genes.
New breast cancer cases outnumber all other
kinds of cancer for women. For 2017, the
latest year for which statistics are available,
the U.S. Centers for Disease Control and
Prevention reported 250, 520 new cases
a year, more than twice as many as the
next-most common cancer, lung and
bronchus. That year 42,000 American
women died of breast cancer.
But those tragic statistics actually
represent a significant improvement in
breast cancer survival rates. The past two
decades have seen a drop in incidence of
ductal carcinoma in situ (DCIS), the type
of breast cancer most likely to develop
into invasive cancer. The American
Cancer Society credits improved detection,
and fewer women taking hormone therapy
for postmenopausal symptoms, for the
reduction. And mortality decreased
40% between 1975 and 2017, thanks to better
treatments as well as earlier detection.
In fact, says Dr. Edison Liu, breast
cancer researcher and president and CEO
of The Jackson Laboratory, “If current
trends continue, theoretically there would
be no breast cancer mortalities by 2045.
And though this remains aspirational
and may not be able to be achieved, the
direction is clear: We are winning.”
JAX breast cancer researcher Edison Liu. JAX photo by Tiffany Laufer.
Creative innovation in treating breast cancers
What were the medical breakthroughs
behind the improvement in prognosis for
women with breast cancer? Liu credits
“decades of creative innovation,” with
each generation of scientists building on
findings of the previous generation.
An important early insight was that cancer
is not a single disease with a single cause,
and that the location of a tumor has less
bearing on disease progression or mortality
than its mechanisms. Better profiling of
breast tumors was the first step in developing
more targeted and effective treatments.
The next big cancer breakthroughs, in
the 1960s, were a combination of
chemotherapy (administering multiple
drugs simultaneously) and adjuvant therapy,
chemotherapy following surgical removal of
a tumor, to eliminate any pockets of residual
disease. Liu notes that adjuvant therapy
was actually pioneered in breast cancer, by
researchers working in the Fondazione IRCCS
Istituto Nazionale dei Tumori in Milan, Italy.
Before adjuvant therapy, Liu says, “The
standard protocol for breast cancer was
draconian surgery followed by draconian
radiation.” And while a small number of
cases still call for such drastic treatment,
“Adjuvant therapy eliminated the terrible
side effects of radical mastectomy
followed by disfiguring radiation that
actually hurt the patient’s health.”
Hormone therapy joined the oncologist’s
toolkit in the 1970s. The hormones estrogen
and progesterone promote the growth of
some breast cancers. The cells of these
hormone-dependent breast cancers contain
proteins called hormone receptors that become activated
when hormones bind to them, causing changes in certain
genes and stimulating cell growth. This therapy to block
the body’s hormone production is aimed at slowing or
stopping the growth of hormone-sensitive tumors.
In 1994 and 1995, researchers identified genetic mutations
in genes, designated BRCA1 and BRCA2, that turned
out to be the most common cause of hereditary breast
cancer. In normal cells, these genes help make proteins
that repair damaged DNA, but mutated versions can
lead to abnormal cell growth and cancer. Since then
close to a dozen other genes have been identified that
are associated with elevated risk for breast cancer.
In 1998, the FDA approved trastuzumab, better known
under the brand name Herceptin, to treat breast
cancers that are HER2-receptor positive. A gene called
HER2 makes HER2 proteins, receptors on breast
cells that normally control how a healthy breast cell
grows, divides and repairs itself. In about 25% of
breast cancers, the HER2 gene goes into production
overdrive, spurring uncontrolled growth and division
of breast cells. Trastuzamab works by binding to
the HER2 receptor and slowing down cell duplication.
The impact of fundamental science on breast cancer
outcome is clear, Liu says, “but equally important is the
contribution of early diagnosis through mammographic
screening. Catching cancer before it metastasizes
saves lives as does adherence to optimal clinical
procedures in the delivery of care.” Now, he adds, with
genetic screening to identify individuals at high risk
for breast cancer, targeted and intensive preventive
measures can further reduce cancer mortality.
“All these may sound incremental,” Liu comments, “but
you add them all up, it becomes akin to building a dam,
brick by brick. And pretty soon you’ve got a pretty effective
dam.” Now, he says, the biggest challenge is improving
the survival of patients with triple-negative breast
cancer — those cancers that are not estrogen-receptor
positive, progesterone-receptor positive or HER2 positive.
JAX breast cancer researcher Francesca Menghi. JAX photo by Tiffany Laufer.
New strategies for tackling triple-negative breast cancers
Triple-negative breast cancers (TNBCs) account for about
15% of all breast cancers, and according to Liu, “is today
the worst breast cancer to have: the fastest‑growing,
the most metastatic.” A study of 50,000 women
with breast cancer showed five-year survival rates
for patients with a TNBC diagnosis at 77%, compared
to 93% for women with other types of breast cancer.
Liu and his lab focus on TNBC. In 2016 the Liu lab published
their discovery of a distinct genomic configuration found
in about half of all triple-negative breast, ovarian and
endometrial cancers, which they dubbed the tandem
duplicator phenotype (TDP). Since then the lab has
published many additional findings on how mutations
in TP53 and BRCA1 genes give rise to the TDP.
The TDP is the result of mutations that cause faulty DNA
replication during cell division. Duplications of short
stretches of copied DNA are inserted in the genome next to
the segments from which they were copied. These tandem
duplication sequences disrupt genes at and near their insertion
points and double the production of genes that happen to
be copied, uninterrupted, in the middle. The Liu lab is now
undertaking a multi-pronged investigation of the TDP.
“We want to understand how the TDP evolves over time,” says
Francesca Menghi, associate research scientist in
the Liu lab. “How do all of these genomic variations occur?
To do this we deploy a combination
of computational analyses, studies in
new mouse models of breast cancer,
and experiments using human cancer
cell lines that are either proficient
or deficient for BRCA1 activity.”
Splicing factor defects and breast cancer
Another category of genetic error may
trigger some breast cancers as well as
many other diseases. A JAX research
team led by Assistant Professor
Olga Anczuków studies splicing
factors, which control the version of
a given gene that is expressed, with
the goal of developing molecules to
correct defects in splicing factors.
In the highly simplified, so-called central
dogma of biology, the genetic instructions
written in DNA are copied (transcribed)
into messenger RNA (mRNA), forming
individual “machines” that each build
one or more proteins — large, complex
molecules that play critical roles in
the body. But there are additional
mechanisms that greatly increase
the potential variety of proteins.
Following transcription, a process
called alternative RNA splicing
enables the creation of different
spliced mRNA versions that, in turn,
can produce proteins with different
functions. “Splicing is like the editing
process in filmmaking,” Anczuków
says. “Just as inserting or deleting
a scene in a movie can change the
movie’s meaning, RNA splicing can
deliver an altered genetic message.”
Not all splices improve the final product,
be it movie or protein. Errors in the
splicing process have been implicated
in many diseases, including cancer.
Anczuków’s lab has shown that a splicing
factor called TRA2B seemed particularly
enriched in TNBC, and now they are
focusing on DNA segments known as
poison-exons, which play a critical
role in maintaining a tight regulation
of splicing-factor levels, which is
necessary for normal cell functions.
Researchers at JAX and UConn Health have
innovated a process to analyze patient
tumors, and identified more than
3,000 splicing events that are specific
to breast tumors. The results, note the
researchers, provide a rich resource
of potential therapeutic targets.
Where are we now?
At her Connecticut-based laboratory, Menghi reflects on how research
in breast cancers, including TNBC, will ultimately
translate into more targeted and effective treatments.
“Every time I talk with my family or friends that don’t have
a scientific background,” she says, “there’s one question
they always ask me: Are we going to cure cancer? And it’s
just so frustrating because in the short term, the individual
discoveries are always really small and incremental.”
To answer the question, she says she explains that the
rise of sequencing technology over the past decade has
enabled an entirely new approach to cancer research and
treatment. “Genome sequencing will open up so much
in terms of our ability to understand what drives tumor
initiation, and as a consequence, our ability to target it,
prevent it, diagnose it early, monitor it better, diagnose
relapses better, stratify patients and find novel treatments.
“I think that this is a time of progress, and I’m
really confident about it,” Menghi says.
Liu adds, “The most gratifying aspect of this is not only
that science has advanced so dramatically, but that all
elements of the scientific community are coordinating
their efforts into providing cures. I have been working
in the field of breast cancer for 30 years, and I have seen
how basic, clinical and epidemiological sciences, when
all work together, have a direct impact on patient lives.”
The rate of advancement is speeding up, Liu says.
“So, perhaps 2045 as the year when breast cancer
mortality ceases is not such a pipe dream.”