Reasons why some breast cancers become resistant to treatment.

Most breast cancers are estrogen receptor-positive, meaning that signals received from estrogen, a hormone, promote the growth of the tumors. To stop these cancers from spreading, estrogen inhibitors are usually prescribed. But what happens when tumors develop treatment resistance?
breast cancer patient considering treatment

In around a third of ER-positive breast cancer cases, the tumors become treatment-resistant. Why is that?

Studies suggest that “approximately 70 percent” of all breast cancers are estrogen receptor-positive (ER-positive).

These types of cancer are typically treated with drugs — such as tamoxifen and fulvestrant — that either lower the levels of the hormone or inhibit the estrogen receptors to prevent the tumors from spreading. This is known as endocrine therapy.

However, around a third of the people treated with these drugs develop resistance to them, which negatively impacts their chances of survival. The mechanisms that underlie the tumors’ resistance to therapy is not well understood and currently poses a major challenge.

Recently, however, specialists from the Dana-Farber Cancer Institute in Boston, MA, have made significant progress in uncovering what exactly happens in the bodies of people in whom endocrine therapy does not work.

Dr. Myles Brown — the director of the Center for Functional Cancer Epigenetics at the Institute — and his colleagues investigated how certain gene mutations render cancer cells more resilient, facilitating metastasis. Their findings, the scientists hope, may eventually lead to more effective approaches for patients who do not respond well to traditional treatments.

The results of the team’s study were published in the journal Cancer Cell.

The mutations that hinder treatment

In a previous study, Dr. Rinath Jeselsohn — who also co-led the new research — and former team saw that mutations of the estrogen receptor gene of cancer cells were largely responsible for the cancer’s resistance to treatment.

On that occasion, the scientists observed these mutations in the metastatic tumors of women who had received endocrine therapy and had not responded to it.

Following on from this discovery, Dr. Jeselsohn and her colleagues analyzed these mutations using laboratory models of ER-positive breast cancer, noting that they supported the cancer’s resistance to the drugs tamoxifen and fulvestrant.

The new study revealed additional mechanisms that researchers had not been aware of previously.

Besides enabling the tumors to adapt to estrogen deprivation, the genetic mutations were also responsible for activating genes that would allow the cancer tumors to spread even further.

Such mutations — which allow genes to gain surprising and novel functions — are referred to as neomorphic mutations.

Therefore, the effect of the genetic mutations is twofold, allowing the cancer tumor to undertake two distinct “lines of attack” at the same time.

“[E]ven though the drug therapies are selecting tumors that can grow without estrogen,” explains Dr. Brown, “the mutations also confer a metastatic advantage to the tumor.”

Combined therapy for resistant cancers

Once they noted the effects of mutations on breast cancer tumors, Dr. Brown and his colleagues turned to modern gene-editing tools — namely, CRISPR-Cas9 — to pinpoint exactly which genes were at the core of estrogen receptor-related alterations.

This revealed that one gene in particular, called CDK7, might lend itself well as a target for new cancer treatments. This gene normally encodes the enzyme cyclin-dependent kinase 7.

Dr. Brown and team took particular interest in the potential of this gene as a target since existing research has already found ways of blocking the expression of CDK7.

Nathanael Gray, also from the Dana-Farber Cancer Institute, experimented with an inhibitor for CDK7 a few years ago. This experimental inhibitor is called THZ1, and it showed potential as an aid for the drug fulvestrant.

The combination of fulvestrant and THZ1 was effective both in cell cultures of ER-positive breast cancer and in animal models of the disease, slowing down tumor growth significantly.

Dr. Brown and his colleagues believe that by putting two and two together, as it were, through the combined findings of all these studies led by the Dana-Farber Cancer Institute, specialists may be able to devise effective treatments for ER-positive breast cancers that don’t respond to endocrine therapy alone.

“These results support the potential of this combination as a therapeutic strategy to overcome endocrine resistance caused by the ER mutants,” the researchers suggest.

Dr. Joy and her colleagues are currently trying to develop appropriate CDK7 inhibitors, and they “hope to test these drugs and develop a clinical trial for patients with ER-positive metastatic breast cancer.”


What!!! -Risk of breast cancer’s return continues long after treatment ends!

A recent analysis has found that even 20 years after receiving a diagnosis of estrogen receptor-positive breast cancer, the risk of the cancer’s return looms large. Should treatment be extended?
Nurse with breast cancer ribbon

A new study brings the length of breast cancer follow-up treatment into question.

Estrogen receptor-positive (ER-positive) breast cancer is the most common breast cancer type, accounting for around 80 percent of all breast cancer cases.

In short, ER-positive breast cancer flourishes in response to estrogen. The standard treatments for this cancer type are tamoxifen, which blocks the effects of estrogen, or aromatase inhibitors, which stop the production of estrogen.

Even once the cancer has gone, these drugs are taken daily for 5 years. Tamoxifen reduces recurrence by half during treatment, and by almost a third in the 5 years following treatment.

Aromatase inhibitors, which will only work in women who are postmenopausal, are even better at reducing the risk of recurrence.

Should treatment be extended?

Over recent years, research has found that extending the length of time that these medications are taken could reduce risks further still. Some cancer researchers are asking whether they should be continued for 10 years.

But these drugs are not without disadvantages. Although side effects are rarely life-threatening, they can substantially impact a woman’s quality of life. Side effects often mimic menopause and include hot flashes, night sweats, mood changes, and vaginal dryness. Aromatase inhibitors also carry an increased risk of osteoporosis, among other conditions.

As the authors of the current study write, “[D]ecisions about extending adjuvant endocrine therapy after 5 years without any recurrence need to balance additional benefits against additional side effects.”

The analysis was carried out by researchers from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). This group has been pooling research into a single dataset since the 1980s, looking at all aspects of breast cancer.

For this study, they took data from 88 clinical trials, including those of 62,923 women with ER-positive breast cancer. Their findings are published this week in the New England Journal of Medicine.

Long-term risk of recurrence

They found that in women who were cancer-free and in therapy for 5 years, a substantial number saw the cancer spread throughout the body over the following 15 years.

Even though these women remained free of recurrence in the first 5 years, the risk of having their cancer recur elsewhere (for example in the bone, liver, or lung) from years 5 to 20 remained constant.”

Senior study author Dr. Daniel F. Hayes

The risk was directly related to the size of the original cancer and the number of lymph nodes that it affected. Specifically, larger cancers and those that affected four or more lymph nodes carried the greatest long-term risks.

Even if the patients were recurrence-free when they stopped the endocrine therapy, they had a 40 percent risk of cancer recurrence within 15 years.

Women whose original cancers were smaller and did not involve the lymph nodes had a 10 percent risk over 15 years.

As lead study author Hongchao Pan, Ph.D. — from the University of Oxford in the United Kingdom — says, “It is remarkable that breast cancer can remain dormant for so long and then spread many years later, with this risk remaining the same year after year and still strongly related to the size of the original cancer and whether it had spread to the nodes.”

Medical News Today got the opportunity to speak to Dr. Hayes, and when asked whether or not he was surprised by the results, he replied, “There have been much smaller studies to suggest this phenomenon […] Our results absolutely validate these and confirm the relentless risk of distant recurrence over the 2 decades after diagnosis.”

What happens next?

The team now wants to understand whether there is a subset of women with ER-positive breast cancer that has a low enough risk so that extended endocrine treatment would not be needed.

Although the analysis took thousands of women into account, the researchers are quick to note that they received their diagnosis decades ago and treatment has since improved. Dr. Hayes told MNT that “it appears that prognosis is better for patients diagnosed over the last 10–15 years.”

He added, “More than half of our patients were entered before 2000, and of course, we only have 20 years of follow-up on patients who were followed for 20 years — so, overall, it is possible that the data in our paper overestimate the absolute risk distant recurrence/year.”

However, we are pretty certain that they do not overestimate the concept that distant recurrences continue without abatement.”

Dr. Daniel F. Hayes

MNT also asked Dr. Hayes about future research to be conducted by the EBCTCG. He said, “There are several ongoing analyses asking a number of questions. We will continue to address issues of the risks of recurrence, and the benefits of various endocrine therapy strategies as we gather more data.”

It is likely that these findings and others like them will be used to advise longer treatment plans for women with more aggressive ER-positive tumors. As Dr. Hayes told us, “[O]ur data will help patients make a better-informed decision.”

Thirst: Our brains tell us when to stop drinking

When the water content of our blood drops, neurons in the brain tell us that we are thirsty. But how do we know when enough is enough?

Water is essential to life. When we get deydrated, it can have serious consequences.

The water content in our body is tightly regulated. Dehydration can lead to dizziness, delirium, and unconsciousness. Drinking fluids restores this balance or homeostasis.

But it takes time for water to travel from our mouths through the body. We stop drinking a long time before this happens.

If we kept drinking during this delay, we would be at serious risk of water intoxication, or water poisoning, which is potentially deadly.

Scientists are beginning to unravel the sophisticated mechanisms that stop us from drinking too much water, and the answer lies in the brain.

What controls thirst?

The brain’s thirst control circuit is a small region in the forebrain called the lamina terminalis (LT).

Once the LT network is activated, we become thirsty. A study published last week in the journal Science demonstrated that thirst creates an uncomfortable feeling in mice, which is alleviated by drinking.

There is one other thing that triggers thirst: eating. As soon as we start to eat, our thirst is stimulated. This is known as prandial thirst.

Water is necessary for us to digest the food that we eat. It also stops electrolytes in food from disturbing homeostasis by balancing out the fluid levels.

Why do we stop drinking?

Zachary A. Knight, Ph.D. – from the Department of Physiology at the University of California, San Francisco – and his team reported in the journal Nature that neurons in the subfornical organ (SFO), which forms part of the LT, might be at the heart of things.

The authors explain that “much normal drinking behavior is anticipatory in nature, meaning that the brain predicts impending changes in fluid balance and adjusts behavior pre-emptively.”

For their study, the researchers used mice and restricted their access to water overnight. “When water was made available,” the authors write, “mice drank avidly and, surprisingly, [SFO] neurons were inhibited within 1 min.”

This drop in neuronal signaling happened much faster than the water was able to reach the blood.

“Drinking resets thirst-promoting SFO neurons in a way that anticipates the future restoration of homeostasis,” they add. This means that our brain anticipates how much water we need to drink to restore homeostasis.

Signals from the mouth to the brain

What is not yet clear is how the brain knows when we are drinking fluids. A recent study published in the journal Nature Neuroscience pointed the finger at receptors in our mouth.

The team – led by Yuki Oka, Ph.D., who is from the Division of Biology and Biological Engineering at the California Institute of Technology in Pasadena – showed that water changes the acid balance in the saliva, which activates acid-taste receptors.

So, what is the best way of quenching thirst? A study by Sanne Boesveldt, Ph.D. – from the Division of Human Nutrition at Wageningen University & Research in the Netherlands – and her team, which will be published in the October edition of the journal Physiology & Behavior, set out to answer this question.

The authors explain that cold drinks are already known to be more thirst quenching, as are sour, flavored, and carbonated drinks.

In their study, the team found that cold, flavored popsicles were significantly more thirst quenching than cold liquids. The most effective flavor was lemon.

So, while the days may be getting colder as fall gets underway in the Northern hemisphere, a lemon popsicle might still be a good option the next time thirst calls.

How does cancer evade the immune system? New mechanism revealed

Cancer’s ability to elude our body’s immune system has long puzzled researchers. The latest study pinpoints one of cancer’s protective cloaks and investigates a way to remove it.
Immunotherapy cancer illustration

Cancer and its interaction with the immune system is a complex story.

Cancer cells are cells that have gone awry; they both multiply unchecked and function incorrectly. Normally, cells that are faulty, dead, or dying are cleared away by the immune system.

Macrophages — a type of white blood cell — are largely responsible for the consumption and destruction of foreign invaders and errant cells.

Although macrophages normally carry out their attacks with ruthless efficiency, some cancer cells manage to evade their roaming gaze. How do cancer cells fly under the immune system’s radar?

In 2009, Dr. Irving Weissman, director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, published research that goes some way toward answering this question. They identified a “don’t eat me” signal on cancer cells.

The first ‘don’t eat me’ signal

Dr. Weissman demonstrated that particularly aggressive cancer cells express higher levels of CD47 — a transmembrane protein — on their cell surface. CD47 binds to a protein called SIRPalpha on the surface of macrophages, reducing their ability to attack and kill the cancer cells.

Studies in animals have shown that treatment with an anti-CD47 antibody significantly increases macrophages ability to kill cancer cells. In some mouse models of cancer, the treatment even led to a cure. Clinical trials are underway to gauge whether this approach will be as successful in humans.

Recently, Dr. Weissman’s team published another paper, outlining research that uncovers another “don’t eat me” signal. This time, the molecule in focus is a cell surface protein called major histocompatibility complex class 1 (MHC class 1).

The researchers found that tumors with higher levels of MHC class 1 on their cell surfaces are more resilient to anti-CD47 treatment.

The role of MHC class 1 in cancer

Adaptive immunity forms the basis of immunological memory — once our immune system has responded to a specific pathogen, if it meets the same intruder again, it can mount a swift and specific response. MHC class 1 are an important part of this wing of the immune system.

MHC class 1 are found on the surfaces of most cells. They take portions of internal cellular proteins and display them on the cell’s surface, providing a snapshot of the cell’s health. If the cell’s protein flags are abnormal, T cells destroy it. This interaction between MHC class 1 and T cells has been well described, but how macrophages are involved was not fully understood.

The current study found that a protein — LILRB1 — on the surface of macrophages binds to a part of MHC class 1 on the surface of cancer cells. Once it has bound, it prevents the macrophage from consuming and killing the cell. This response was seen both in a laboratory dish and in mice with human tumors.

By inhibiting the CD47-mediated pathway and the LILRB1 pathway, interfering with both “don’t eat me” signals, tumor growth was significantly slowed in mice. The results are published this week in Nature Immunology.

Simultaneously blocking both these pathways in mice resulted in the infiltration of the tumor with many types of immune cells and significantly promoted tumor clearance, resulting in smaller tumors overall.”

Amira Barkal, graduate student, joint lead author

Barkal continues, “We are excited about the possibility of a double- or perhaps even triple-pronged therapy in humans in which we combine multiple blockades to cancer growth.”

The future of immunotherapy

Immunotherapy for cancer is a rapidly developing field, but the story is a complex one. Different cancers have different immunological fingerprints; for instance, some human cancer cells reduce the levels of MHC class 1 on their cell surface, helping them to evade T cells.

Individuals with these cancers might not respond particularly well to therapies designed to enhance T cell activity. However, these cancers might be more vulnerable to an anti-CD47 approach. This also works the other way around, cancers with plentiful MHC class 1 might be less affected by anti-CD47 treatment.

Uncovering how cancer cells avoid cell death and understanding how these pathways might be overturned is a difficult but critical endeavor. This study marks another step toward teaching our immune system how to slow cancer’s march.

The state of cancer: Are we close to a cure?

Cancer is the leading cause of death across the globe. For years now, researchers have led meticulous studies focused on how to stop this deadly disease in its tracks. How close are we to finding more effective treatments?
researchers in the labHow far has cancer research come?

The World Health Organization (WHO) note that, worldwide, nearly 1 in 6 deaths are down to cancer.

In the United States alone, the National Cancer Institute (NCI) estimated 1,688,780 new cancer cases and 600,920 cancer-related deaths in 2017.

Currently, the most common types of cancer treatment are chemotherapy, radiotherapy, tumor surgery, and — in the case prostate cancer and breast cancer — hormonal therapy.

However, other types of treatment are beginning to pick up steam: therapies that — on their own or in combination with other treatments — are meant to help defeat cancer more efficiently and, ideally, have fewer side effects.

Innovations in cancer treatment aim to address a set of issues that will typically face healthcare providers and patients, including aggressive treatment accompanied by unwanted side effects, tumor recurrence after treatment, surgery, or both, and aggressive cancers that are resilient to widely utilized treatments.

Below, we review some of the most recent cancer research breakthroughs that give us renewed hope that better therapies and prevention strategies will soon follow suit.

Boosting the immune system’s ‘arsenal’

One type of therapy that has attracted a lot of attention recently is immunotherapy, which aims to reinforce our own bodies’ existing arsenal against foreign bodies and harmful cells: our immune system’s response to the spread of cancer tumors.

But many types of cancer cell are so dangerous because they have ways of “duping” the immune system — either into ignoring them altogether or else into giving them a “helping hand.”

Therefore, some types of aggressive cancer are able to spread more easily and become resistant to chemotherapy or radiotherapy.

However, thanks to in vitro and in vivo experiments, researchers are now learning how they might be able to “deactivate” the cancer cells’ protective systems. A study published last year in Nature Immunology found that macrophages, or white blood cells, that are normally tasked with “eating up” cellular debris and other harmful foreign “objects” failed to obliterate the super-aggressive cancer cells.

That was because, in their interaction with the cancer cells, the macrophages read not one but two signals meant to repel their “cleansing” action.

This knowledge, however, also showed the scientists the way forward: by blocking the two relevant signaling pathways, they re-enabled the white blood cells to do their work.

Therapeutic viruses and innovative ‘vaccines’

A surprising weapon in the fight against cancer could be therapeutic viruses, as revealed by a team from the United Kingdom earlier this year. In their experiments, they managed to use a reovirus to attack brain cancer cells while leaving healthy cells alone.

“This is the first time it has been shown that a therapeutic virus is able to pass through the brain-blood barrier,” explained the study authors, which “opens up the possibility [that] this type of immunotherapy could be used to treat more people with aggressive brain cancers.”

Another area for improvement in immunotherapy is “dendritic vaccines,” a strategy wherein dendritic cells (which play a key role in the body’s immune response) are collected from a person’s body, “armed” with tumor-specific antigens — which will teach them to “hunt” and destroy relevant cancer cells — and injected back into the body to boost the immune system.

In a new study, researchers in Switzerland identified a way to improve the action of these dendritic vaccines by creating artificial receptors able to recognize and “abduct” tiny vesicles that have been linked to cancer tumors’ spread in the body.

By attaching these artificial receptors to the dendritic cells in the “vaccines,” the therapeutic cells are enabled to recognize harmful cancer cells with more accuracy.

Importantly, recent studies have shown that immunotherapy may work best if delivered in tandem with chemotherapy — specifically, if the chemotherapy drugs are delivered first, and they are followed up with immunotherapy.

But this approach does have some pitfalls; it is difficult to control the effects of this combined method, so sometimes, healthy tissue may be attacked alongside cancer tumors.

However, scientists from two institutions in North Carolina have developed a substance that, once injected into the body, becomes gel-like: a “bioresponsive scaffold system.” The scaffold can hold both chemotherapy and immunotherapy drugs at once, releasing them systematically into primary tumors.

This method allows for a better control of both therapies, ensuring that the drugs act on the targeted tumor alone.

The nanoparticle revolution

Speaking of specially developed tools for delivering drugs straight to the tumor and hunting down micro tumors with accuracy and efficiency, the past couple of years have seen a “boom” in nanotechnology and nanoparticle developments for cancer treatments.

nanoparticlesNanoparticles could be ‘a game-changer’ in cancer treatment.

Nanoparticles are microscopic particles that have garnered so much attention in clinical research, among other fields, because they bring us the chance to develop precise, less invasive methods of tackling disease.

Vitally, they can target cancer cells or cancer tumors without harming healthy cells in the surrounding environment.

Some nanoparticles have now been created to provide very focused hyperthermic treatment, which is a type of therapy that uses hot temperatures to make cancer tumors shrink.

Last year, scientists from China and the U.K. managed to come up with a type of “self-regulating” nanoparticle that was able to expose tumors to heat while avoiding contact with healthy tissue.

“This could potentially be a game-changer in the way we treat people who have cancer,” said one of the researchers in charge of this project.

These tiny vehicles can also be used to target cancer stem-like cells, which are undifferentiated cells that have been linked to the resilience of certain types of cancer in the face of traditional treatments such as chemotherapy.

Thus, nanoparticles can be “loaded” with drugs and set to “hunt down” cancer stem cells to prevent the growth or recurrence of tumors. Scientists have experimented with drug-filled nanoparticles in the treatment of various types of cancer, including breast cancer and endometrial cancer.

No less importantly, minuscule vehicles called “nanoprobes” can be used to detect the presence of micrometastases, which are secondary tumors so tiny that they cannot be seen using traditional methods.

Dr. Steven K. Libutti, director of the Rutgers Cancer Institute of New Jersey in New Brunswick, calls micrometastases “the Achilles’ heel of surgical management for cancer” and argues that nanoprobes “go a long way to solving [such] problems.”

Tumor ‘starvation’ strategies

Another type of strategy that researchers have been investigating of late is that of “starving” tumors of the nutrients they need to grow and spread. This, scientists point out, could be a saving grace in the case of aggressive, resilient cancers that cannot effectively be eradicated otherwise.

illustration of microscope and syringes

One novel method of ‘attacking’ cancer is by ‘starving’ cancer cells to death.

Three different studies — whose results were all published in January this year — looked at ways of cutting off cancers’ nutritional supplies.

One of these studies looked at ways of stopping glutamine, a naturally occurring amino acid, from feeding cancer cells.

Certain cancers, such as breast, lung, and colon, are known to use this amino acid to support their growth.

By blocking cancer cells’ access to glutamine, the researchers managed to maximize the impact of oxidative stress, a process that eventually induces cell death, on these cells.

Some aggressive types of breast cancer may be halted by stopping the cells from “feeding” on a particular enzyme that helps them to produce the energy they need to thrive.

Another way of depleting cancer cells of energy is by blocking their access to vitamin B-2, as researchers from the University of Salford in the U.K. have observed.

As one study author says, “This is hopefully the beginning of an alternative approach to halting cancer stem cells.” This strategy could help individuals receiving cancer treatment to avoid the toxic side effects of chemotherapy.

Cancer treatments and epigenetics

Epigenetics refers to the changes caused in our bodies by alterations in gene expression, which dictate whether certain characteristics appear or if certain “actions” are affected at a biological level.

According to research that addressed the impact of such changes, many cancers, as well as the behaviors of cancer cells, are determined by epigenetic factors.

“Recent advances in the field of epigenetics have shown that human cancer cells harbor global epigenetic abnormalities, in addition to numerous genetic alterations.”

These genetic and epigenetic alterations interact at all stages of cancer development, working together to promote cancer progression.”

Thus, it is crucial for specialists to understand when and where to intervene and the expression of which genes they may need to switch on or off, depending on their role in the development of cancer.

One study, for instance, found that the gene responsible for the advent of Huntington’s disease produces a set of molecules whose action may actually prevent cancer from occurring.

Now, the researchers’ challenge is to channel the therapeutic potential of this process without triggering Huntington’s disease. However, the scientists are hopeful.

“We believe a short-term treatment cancer therapy for a few weeks might be possible,” says the study’s senior author.

Another recent study was able to establish that estrogen-receptor positive breast cancers that become resistant to chemotherapy gain their resilience through genetic mutations that “confer a metastatic advantage to the tumor.”

But this knowledge also gave researchers the “break” that they needed to come up with an improved treatment for such stubborn tumors: a combination therapy that delivers the chemotherapeutic drug fulvestrant alongside an experimental enzyme inhibitor.

What does this all mean?

Cancer research is running at full speed, taking advantage of all the technological advances that science has achieved over recent years. But what does that mean in terms of coming up with a cure for cancer?

Whether or not there will ever be a cure for all cancer types is currently a matter of strong debate; although promising studies are published and covered by the media almost every day, cancer types vary immensely.

This makes it very difficult to say that an approach that works for one type will be adaptable to all.

Also, while there is much emerging research promising more effective treatments, most of these projects are still in their early stages, having conducted in vitro and in vivo experiments. Some potential treatments still have a long way to go before clinical trials in human patients.

Still, that doesn’t mean we should lose all hope. Some researchers explain that these efforts should make us optimistic; while we may not be at the stage where we can claim that cancer can easily be eradicated, our furthered knowledge and ever more precise tools keep us ahead of the game and improve our odds in the fight against this disease.

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