for many years researchers have been trying

March 1, 2024

11 min read

These Cancers Were Beyond Treatment—But Might Not Be Anymore

New drugs called antibody-drug conjugates help patients with cancers that used to be beyond treatment

By Jyoti Madhusoodanan

Keith Negley

I n the long and often dispiriting quest to cure cancer, the 1998 approval of the drug Herceptin was a tremendously hopeful moment. This drug for breast cancer was the first to use a tumor-specific protein as a homing beacon to find and kill cancer cells. And it worked. Herceptin has benefited about three million people since that time, dramatically increasing the 10-year survival rate—and the cancer-free rate—for what was once one of the worst medical diagnoses. “Honestly, it was sort of earth-shattering,” says oncologist Sara M. Tolaney of the Dana-Farber Cancer Institute in Boston.

But the drug has a major limitation. Herceptin’s beacon is a protein called HER2, and it works best for people whose tumors are spurred to grow by the HER2 signal—yet that’s only about one fifth of breast cancer patients. For the other 80 percent of the ap­­prox­i­mate­ly 250,000 people diagnosed with the disease every year in the U.S., Herceptin offers no benefits.

The hunt for better treatments led researchers to reimagine targeted therapies. By 2022 they had developed one that linked Herceptin to another cancer-killing drug. This therapy, for the first time, could damage tumors that had vanishingly low levels of HER2. The drug, named Enhertu, extended the lives of people with breast cancer by several months, sometimes longer. And it did so with fewer severe side effects than standard chemotherapies. The U.S. Food and Drug Administration approved its use in that year.

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The news got even better in 2023. Researchers reported that Enhertu appeared to work even on tumors with seemingly no HER2 at all. (It’s possible the cancers did have the protein but at very low levels that escaped standard detection methods.) “Exciting!” says oncologist Shanu Modi of Memorial Sloan Kettering (MSK) Cancer Center in New York City, who helped to run the study that led to Enhertu’s approval. “They did this provocative test and saw this almost 30 percent response rate” in tumors apparently lacking the cancer protein, she notes.

“Almost every patient who was enrolled on that drug had benefits. It was really so satisfying.” —Shanu Modi, MSK Cancer Center

Enhertu belongs to an ingenious and growing class of targeted cancer drugs called antibody-drug conjugates, or ADCs. The compounds are built around a particular antibody, an immune system protein that homes in on molecules that are abundant on cancer cells. The antibody is linked to a toxic payload, a drug that kills those cells. An ADC’s affinity for cancer means it spares healthy cells, avoiding many of the side effects of traditional chemotherapy. And each antibody can be paired with several different drugs. This Lego-like assembly opens up a world of mix-and-match possibilities. Researchers can use the same drug to treat many cancers by switching up the antibody, or they can attack one type of tumor with many different ADCs that target several cancer biomarkers on the cells. This ability “changes the way we think about drug development,” Tolaney says.

The idea for ADCs is not entirely new—the first one was cleared for patient use in 2000—but recently scientists have learned intricate chemical construction techniques that make the compounds much more effective, and they have identified new cancer-specific targets. These advances have driven a wave of new development. At least 14 ADCs have been approved for breast, bladder, ovarian, blood, and other cancers. Approximately 100 others are in the preclinical pipeline. One ADC for breast cancer, known as T-DM1, proved much more effective than Herceptin and has become the standard of care for early stages of disease. “It is pretty cool to see how things have changed so quickly,” Tolaney says.

Buoyed by the successes, researchers and pharmaceutical companies are pouring resources into developing more powerful ADCs—perhaps even ones that can work across a wide range of cancer types. Pharma giants such as Gilead, Roche and BioNTech have invested heavily in their ADC programs; in October 2023, for example, Merck put $4 billion into a partnership with Daiichi Sankyo, the biotechnology firm that partnered with AstraZeneca to produce Enhertu.

But the new drugs are still beset by some mysterious problems. Some ADCs have side effects similar to those caused by traditional chemotherapies—which shouldn’t happen, because the drugs are supposed to target cancer cells alone. On patient forums, people describe needing to reduce their doses because of intolerable nausea or fatigue. These drawbacks limit ADCs’ use, so scientists and pharma companies are urgently trying to figure out what is causing them.

In the clinical trial that led to Enhertu’s ap­­prov­al, patients typically had already received different kinds of chemotherapy drugs, such as medications that stop cells from multiplying. But these drugs—and other forms of chemotherapy—do not distinguish between a cancer cell and a healthy one. Any cell trying to make DNA or multiply is vulnerable, and normal tissue and tumors can both be attacked. Fully 64 percent of people on standard chemotherapy experience nausea, diarrhea, fatigue, and other negative side effects. For many, these can be as debilitating as cancer itself. Such effects limit the dose people can take and the length of treatment, leaving windows of opportunity for tumors to grow resistant and rebound.

For many years researchers have sought less toxic alternatives, envisioning precision drugs that target cancers and spare healthy cells. The idea of ADCs sprang from the exquisite specificity of antibodies. If highly toxic forms of chemotherapy could be strapped onto antibodies, the toxins would reach only the cancer cells and no others. Although the concept was straightforward, attempts at making ADCs faltered for decades.

Some of the earliest attempts used drugs that just weren’t strong enough. In the 1950s, for instance, researchers linked a drug named methotrexate to an antibody that targets carcinoembryonic antigen, a common tumor marker, and tested whether the construct could treat advanced colorectal and ovarian cancers in people. The drug bound to its target but had little therapeutic effect. Researchers then swung too far to the other end of the spectrum and tried using much more toxic drugs instead. But these drugs triggered serious side effects.

Jen Christiansen; Graphics consultant: Greg Thurber/University of Michigan

Greg Thurber, a chemical engineer at the University of Michigan, looked into this conundrum. He began working on ADCs when studying how antibodies spread through the body to bind to their targets. After ADCs infiltrate a tumor through its network of blood vessels, the compounds slip out of these vessels and into cancer cells to kill them, Thurber says. But the ADCs that existed at the time never got past the cells just outside the blood vessels. They bound too tightly. The key to improved effects, it turned out, was tailoring the antibody parts so they zeroed in on cancer cells but had a loose enough grip for some to slip into the interior of the tumor. “A lot of people in the field had a very simple concept—we put a chemotherapy drug on an antibody, it targets it to the cancer cell, and it will avoid healthy tissue,” Thurber says. “That’s not at all how they work in reality.”

Tinkering with the drug component of ADCs, as well as the antibody, eventually led to a cancer-killing sweet spot. In 2013 the fda greenlit T-DM1 for breast cancer. Its antibody is trastuzumab (the “T” in T-DM1), the same antibody used in Herceptin. The drug attached to this antibody is notable because it’s too dangerous to be used on its own. Known as emtansine, it was initially discovered in the 1970s but shelved because it was too toxic to too many cells. Tethered together as T-DM1, however, the drug and antibody generally stayed away from healthy cells and proved to be a potent and precise combination.

In the early 2000s Modi helped to conduct a trial of T-DM1—branded Kadcyla by its maker, Genentech—in people who had an especially difficult disease: advanced HER2-positive breast cancer that had spread throughout the body. Only those who had run out of other treatment options were enrolled. “We were taking people who in some cases were really looking to go to hospice,” Modi says. Yet “almost every patient who was enrolled on that drug had benefits. It was really so satisfying.”

In another trial of about 1,500 people with early breast cancer, an interim data analysis, published in 2019, estimated that 88 percent of those who received T-DM1 would be cancer-free three years later, compared with just 77 percent of those who received Herceptin alone. The drug has proved “more active than most of the therapies we were giving to patients, and it was associated with a better safety profile,” Modi says.

Kadcyla’s success against difficult-to-treat cancers didn’t just transform some patients’ lives. It pumped enthusiasm—and, perhaps more important, pharmaceutical industry dollars—into the idea of ADCs. Re­­search­ers now knew that with things pieced together correctly, it was possible to load an antibody with drugs too toxic to be used otherwise and produce a medicine that worked better than traditional chemotherapy.

Several similarly designed ADCs have been ap­­proved for a range of different cancer types. Many of these carry drugs that inhibit the enzyme topoisomerase 1, which is essential for DNA replication. Like em­­tan­sine, the drug used in Kadcyla, newer topo­isomerase inhibitors are too toxic to be used as freestanding drugs but are much less harmful when they’re largely restricted to tumor cells. And Kadcyla itself, after being shown to slow or stall late-stage breast cancer, is being tested on patients with very early-stage disease to see whether treatment at that point can not only slow cancer down but actually cure it. Its success “was sort of the catalyst for continued exploration,” Modi says. “Can we build on this? Can we do even better?”

D oing better, it turns out, involves designing good linker molecules that tie the antibody to the drug. These tiny structures act like chemical triggers. They must remain perfectly stable until they reach their target, then unclip from the antibody to discharge their payload at the tumor. Some of the earliest attempts at making ADCs failed not because of the antibodies or drugs used but as a result of unstable linkers.

Modern ADCs rely on two types of linkers. One kind remains unbroken even when the ADC reaches its target. The other kind, known as cleavable linkers, are chemicals that break in response to very specific cues, such as enzymes that are abundant in tumors, in the spaces between individual cancer cells. Once an ADC is within the tumor’s boundaries, these enzymes cleave the linker and release the drug payload.

Cleavable linkers are showing impressive advantages, and more than 80 percent of currently approved ADCs now use them. An ADC with a noncleavable linker will kill only the cell it attaches to, but one that splits up could place drug molecules near neighboring tumor cells and destroy them as well. This so-called bystander effect can make the drugs much more effective, Thurber says.

Enhertu, for instance, uses the same antibody as Kadcyla but with a cleavable linker (Kadcyla uses a noncleavable version) and a different drug. Each Enhertu antibody carries approximately eight drug molecules, compared with about three per antibody in Kadcyla. In one study, researchers compared the effects of these two treatments in people with HER2-positive breast cancers. Enhertu was the clear winner. It stopped tumor growth for more than two years on average, whereas Kadcyla did so for just six months. “It was a landslide in terms of how much better it was,” Tolaney says. “It’s a really nice example of how ADC technology leads to dramatic differences in outcomes.”

The bystander effect also explains, in part, why Enhertu is effective against tumors that have barely any HER2: once the ADC enters a tumor and the drug molecules detach, they can kill neighboring tumor cells even if those bystanders don’t carry much HER2 on their surface. This action, along with the use of a diagnostic test that can miss extremely low HER2 levels, could explain the results from the trial where the drug seemed to work on tumors with no HER2. That trial employed an assay known as an IHC test. It is generally used to categorize cancers as HER2 positive or negative, not to measure the amount of the protein present. A negative result typically means 10 percent or fewer of the tumor’s cells have HER2 on their surfaces. Yet 10 percent may be enough to attract a few Enhertu particles, and the bystander effect might be sufficient to destroy tumor cells, Modi says.

Enhertu is not the only ADC that appears to work this way. In a 2022 study, researchers found that Trodelvy, an ADC that targets a surface protein known as TROP2, seemed to be more effective than standard chemotherapy for people with metastatic triple-negative breast cancer, a particularly hard-to-treat disease. Trodelvy was better irrespective of how much or how little TROP2 was detected on tumors. “That, to me, is wild,” Tolaney says. “We’re excited about it because these cancers are having benefits [apparently] without the target.”

This new generation of ADCs is making a difference in other types of cancers previously thought to be intractable, such as metastatic bladder cancer. In 2021 the fda approved Trodelvy and another ADC named Padcev to treat this illness. For 30 years the standard of care for this type of bladder cancer was chemotherapy alone, says oncologist David J. Benjamin, who treats genitourinary cancers at Hoag Family Cancer Institute in southern California. “Now we have multiple new treatments, and two of them happen to be antibody-drug conjugates,” Benjamin says. In clinical trials for patients with advanced bladder cancer, Padcev combined with a drug that stimulates the immune system shrank tumors or stalled their growth in more than 60 percent of people. In a whopping 30 percent of those who received the two-drug combination, their cancer completely disappeared—an unprecedented success.

But even newer ADCs aren’t without problems. The bystander effect, which makes them so effective, can spread far enough from the tumor to affect healthy cells, causing hair loss, nausea, diarrhea, fatigue, and other side effects that are disturbingly similar to the fallout of old-school chemo. ADCs also have been linked to a variety of eye problems ranging from conjunctivitis to severe vision loss.

Another explanation for these nasty effects is that there are no protein targets that are exclusive to cancer cells. These proteins, also known as antigens, are more abundant in cancers but may appear in normal cells. That makes some binding of ADCs to healthy cells unavoidable. “I can’t think of any examples of true tumor-specific antigens,” says Matthew Vander Heiden, a molecular biologist at the Koch Institute at the Massachusetts Institute of Technology. Further, ADCs, like any other medicine or antibody, are eventually ingested and metabolized by noncancerous cells. This process fragments them into smaller pieces, releasing payload drugs from their linkers and triggering reactions.

Still, the ability to take ADCs apart and tweak their components—something that isn’t possible with traditional treatments—offers researchers the chance to find versions with fewer side effects and more advantages. At present, most ADCs are used at the maximum dose a person can tolerate. That might not be true with future versions. When developing a medication, whether it’s a simple painkiller, a chemotherapy or an ADC, researchers begin by figuring out the lowest dose at which the drug is effective. Then they work out the highest dose that people can receive safely. The space between those two doses, known as a therapeutic window, is usually small. But the ability to swap components offers ADC researchers many routes to widening it. Eventually drugmakers might create ADCs so effective that patients never need to take the highest tolerable dose—a much lower one would eliminate tumors without creating unintended consequences such as nausea or hair loss.

Shifting away from toxic chemotherapy-based drugs as payloads could also reduce side effects in patients. Some approved ADCs, for instance, link antibodies to drugs that can activate the body’s own immune system to attack cancer cells rather than relying on cell-poisoning chemicals. In addition, scientists are exploring ways to deliver radiation therapy di­­rectly to tumors by tethering antibodies to radioisotopes. Joshua Z. Drago, an oncologist at MSK Cancer Center, says that with the right kind of linkers, ADCs “could theoretically deliver any kind of small-molecule medication.”

Ultimately, recombined and improved components could lead to the type of swap that cancer pa­­tients really care about: exchanging their disease for a cure.

Jyoti Madhusoodanan  is a health and science journalist based in Portland, Ore. She has a Ph.D. in microbiology.

Why haven't we cured cancer yet?

Billions of pounds have been raised, invested and spent on cancer research over many decades, but we still haven’t cured cancer. We asked our experts to explain just why that is - and why we still urgently need to fund more cancer research.

As a researcher and doctor who has seen first-hand the lifesaving potential of new targeted therapies for cancer, my opinion is that we are far from helpless in the face of cancer. While individual cancer diagnoses remain one of the scariest conversations people can have with their doctor; it is worth stepping back to look at the bigger picture. Over the last 40 years, research has made astonishing progress and survival rates for many cancers have increased dramatically over the last decades. Survival rates for many cancers have soared.

It's important to remember that we have  come a long way - overall, cancer survival in the UK has doubled in the last 40 years.

In the 1970s only 25% of people with cancer would survive 10 years or more after their diagnosis. Today that figure is 50%. But cancer is a complex disease - and the fact is that we won't ever find one single cure. Here's why:

Cancer is not just one disease

To understand why we haven’t cured cancer yet, the most important thing to know is that cancer is not one disease. Instead, it’s an umbrella term for more than 200 distinct diseases – that’s why we fund research into any type of cancer.

Each broad cancer type has many sub-types, and they all look and behave differently because they are different on a genetic and molecular level. This is because cancer arises from our own cells, so each cancer can be as different and diverse as people are.

Myriads of mutations exist

Underlying the more than 200 different cancers are a myriad of different genetic mutations. Every cancer is caused by a different set of mutations and as the tumour grows, more and more mutations accumulate. This means that every tumour has an individual set of mutations, so a drug that works for one cancer patient, might have absolutely no effect on another.

That’s why we fund researchers like Dr Diego Pasini in Italy, whose research project aims to understand why a particular mutation makes some cancers more likely to develop.

Cancer cells within a single tumour are not identical

Not every cancer cell in a tumour will have the same genetic mutations as a neighbouring cancer cell. That means that treatments can often kill one type of cell in a tumour, while others survive the treatment, allowing the tumour to grow again.

Treatments can eventually stop working

The genetic mutations that cancer cells acquire over time mean that the cells change the way they behave. This can be an incredibly difficult problem during treatment because the mutations can lead to cancer cells developing resistance to a treatment over time, making it ineffective.

If that happens, the patient will then have to be put on to a different treatment – but again, the cancer could develop resistance to the new drug. This is why we fund researchers like Maite Huarte, who is trying to figure out how to overcome this resistance.

Cancer cells are really good at staying alive

Normal cells have certain mechanisms in place that stop them from growing or dividing too much. Cancer cells have lost these control mechanisms and can develop an arsenal of tricks to avoid being killed.

That’s why we fund researchers like Vincenzo Giambra, who aims to understand how cancer cells become such survival experts.

We cannot fund more vital research without the support of Curestarters like you. Together we can save lives by discovering new cures for all types of cancer. Will you join us today? 

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Cancer Research Insights from the Latest Decade, 2010 to 2020

In the last 10 years, the overall cancer death rate has continued to decline. Researchers in the US and across the world have made major advances in learning more complex details about how to prevent, diagnose, treat, and survive cancer. At the forefront of emerging cancer research is the success of immunotherapy, the growing role of precision medicine, the influence that reducing health disparities can have on cancer outcomes, and the development and use of liquid biopsies and machine learning, which is allowing scientists to make sense of “big data.” Here’s a look at some of the significant advances from the past 10 years that are helping to save lives now – and how ACS research has contributed to each one.  

Treating Cancer Became More Precise

Precision medicine is helping move cancer treatment from one-size-fits-all to an approach where doctors can choose treatments that are most likely to successfully treat a person’s cancer based on the detailed genetic information of that person’s specific cancer. With advances leading to faster and less expensive gene sequencing, precision medicine is starting to be used more often to treat patients, most notably in the treatment of lung cancer. Over the last 10 years, many researchers with ACS grants have contributed to that growth. For instance, ACS-funded researchers across the US have developed ways to quickly analyze the large amounts of data that result from gene sequencing, identify mutations in lung cancer genes , and helped find new treatments for lung cancer patients when the precision drug they were using stopped working. ACS also helped fund research on precision medicines for triple negative breast cancer , pancreatic cancer , certain brain cancers , and other types of cancer. 

Cancers Can Spread With Help From Their Neighbors

Once cancer spreads (metastasizes) from one place in the body to another, the chances of survival decrease. Until recently, scientists haven’t known how much help cancer cells get from other types of cells and substances in their microenvironment. The microenvironment is the immediate area around the tumor. Over the last 10 years, ACS grantees defined features of cancer cells that must be present for metastasis to happen. They also learned more about how cancer cells:

• send and receive signals that change the microenvironment to “clear a path” to the new site of spread
• change to avoid attack from the immune system
• are able to create a new tumor
• thrive in a new location

Identifying each “helper” in the microenvironment could lead to new targets for novel treatments that can help shut down the cancer’s growth and ability to spread.

Two New Types of Immunotherapy Were Developed

CAR T-cell therapy (also called gene therapy) involves making changes to a patient’s T cells (a type of immune cell) in the lab so they can better fight cancer. The ACS helped fund some of the pioneering research involved in the development and improvement of Kymriah (tisagenlecleucel), the first gene therapy approved by the FDA. This drug can be used to treat leukemia and lymphoma in children and adults.

Immune checkpoint inhibitors are another type of immunotherapy. They stop cancer cells from “hiding” from the immune system. But over time, patients develop resistance to these drugs, and ACS grantees are finding solutions. They’ve found that:

• Certain DNA changes in melanoma tumors can predict resistance to immunotherapy.
• The more a non-small cell lung cancer tumor’s DNA changes , the more likely it is to respond to immunotherapy—especially when it’s combined with other treatments.
• Researchers can adapt immunotherapies as the cancer cells adapt and stop responding to drugs.

More People Started Getting the Message that Obesity Is Linked with Cancer

Obesity is now the second-leading cause of preventable cancer deaths in the US. There’s clear evidence that excess weight increases the risk for developing cancer , but research continues in order to better understand the full effect obesity has on cancer. In 2016, the ACS Cancer Prevention Study-II (CPS-II) linked excess weight with 13 types of cancers . Here are some other key findings from ACS research related to obesity:

• People who follow cancer prevention guidelines , including maintaining a healthy weight may lower their risk for developing cancer.
• The rates of 6 obesity-related cancers are rising faster among adults under age 50 than among older adults in the US.
• Data from the CPS-II Nutrition Survey showed that obesity before, but not after , a diagnosis of colorectal cancer was associated with an increased risk of death.
• Losing weight after age 50 may reduce a woman’s risk of developing breast cancer.

Smoking Is Still the Most Preventable Cause of Cancer Deaths

Though fewer people use tobacco worldwide, smoking remains the leading cause of preventable deaths from cancer. In the past decade, ACS researchers have continued pioneering studies on the complexities of tobacco economics, showing that higher taxes on cigarettes reduce smoking and that increasing such taxes in states where they are still low could save lives. ACS researchers also found that illicit trade and harm to tobacco farmers are mostly myths sustained by the tobacco industry to stop public health efforts. The Surgeon General used ACS data to help show the far-reaching damage from smoking includes associations with breast and prostate cancer , as well as kidney failure, hypertension, infections, and respiratory diseases. In 2013, ACS research showed that women’s risk of dying from smoking had caught up to men’s .

Researchers Discover More About the Microbiome’s Influence on Cancer

The microbiome is a complex community of microorganisms like bacteria, fungi, and viruses that live on and in our bodies. When there’s a healthy mix of these microorganisms, they do a variety of tasks like help our immune system function, and help our bodies digest food and absorb nutrients. But when the mix becomes out of balance, it may lead to disease, including cancer. Recently, researchers discovered that an unbalanced microbiome may influence metastasis, the spread of cancer to distant parts of the body. For example, in 2017, ACS research found that Fusobacterium travels with colon cancer cells as they metastasize. This close pairing of bacteria and cancer cells gives researchers an exciting opportunity to test whether antibiotics may help patients with Fusobacterium -associated colorectal cancer. ACS research has also contributed greatly to understanding the microbiome’s role in immunotherapies , especially for melanoma .

DNA Mutations Aren’t the Only Causes of Cancer

Epigenetics refers to changes in how genes behave that don’t involve changes to the gene itself. Put more simply, you can think of cells as actors , and DNA as the script, which includes the stage directions about key actions. Epigenetics would be like directing. The script (DNA) may be the same, but the director is able to change the movie for better or worse. Both gene changes and epigenetic changes can be involved with cancer. In the last 10 years, ACS-funded researchers have been on the forefront of epigenetics research. Some of their findings include:

• Many types of cancers are associated with epigenetic changes.
• Epigenetic changes alone may be involved in cancer even when there are no genetic changes.
• Genes can be controlled by tiny pieces of RNA , called microRNA, that contribute to the development of a tumor and to its spread.
• MicroRNAs may be targets for new anti-cancer drugs.

Health Equity Matters

Health equity is the idea that everyone has a fair and just opportunity to prevent, find, treat, and survive cancer. Tracking health disparities, a difference in health that’s closely linked with an economic, social, or environmental disadvantages, is a way to measure progress toward achieving health equity. In the last 10 years, ACS-funded research has studied a range of causes for healthcare disparities and a diverse set of health equity issues. Some of their key findings include:

• Inequalities of cancer care due to social and economic issues are increasing.
• States that have expanded Medicaid under the Affordable Care Act had much lower disparities among minorities, people in poverty, and those in rural areas.
• Younger, uninsured adults are more likely to be diagnosed with cancer at a later stage, when the cancer has already spread, and more likely to have financial problems related to health care.
• Structural racism has significant effects on health disparities in the US. Structural racism refers to all the ways societies allow racial discrimination to continue though systems of housing, education, employment, earnings, benefits, credit, media, health care, and criminal justice.

New Understanding About Cancer Cells’ Metabolism Opens the Door for New Drug Targets

Like normal cells, cancer cells grow by using metabolic processes to convert “food” (carbohydrates, fats, and proteins) into energy. But cancer cells have abnormal metabolisms that help them multiply and spread quickly. Over the last 10 years, ACS-funded researchers have been actively involved in work that could lead to the development of drugs that could kill cancer cells by interfering with their metabolism. Here are some of the potential new drug targets they’ve discovered.

• A protein in a cancer cell that’s abnormal. This protein is made by a mutated gene. Normally, it keeps tumors from growing. But when the protein comes from a mutated gene, it does the opposite and helps a tumor grow. A drug that targets this protein could slow a cancer’s growth.
• A type of amino acid . Amino acids are one type of fuel used by cancer cells to grow, and it may be particularly important for pancreatic cancer. A drug that targets this amino acid could cut off a “food” supply to the cancer.
• The mutated genes in a cancer cell that make an abnormal enzyme . This enzyme is part of the machinery cells use to turn food into energy. Drugs that target this gene in cancer metabolism may help treat some difficult-to-treat cancers, including certain brain or spinal tumors (gliomas) and cancer in the bile duct (cholangiocarcinoma).
• The gene that’s activated in areas where there’s too little oxygen . This often happens when cancer cells are growing very rapidly. A drug that targets this gene could prevent cancer from surviving in such areas.

Researchers Highlighted the Benefits of Receiving Palliative Care Early in Cancer Treatment

With cancer, there are two modes of care—treatment directed at the disease and treatment, known as palliative care, which is focused on the person with the disease. This type of care helps patients and caregivers manage symptoms from the cancer and side effects from the treatment. Clinical trials have shown that when people with cancer receive both types of treatment at the same time, their symptoms are controlled better, and they have less anxiety and depression, improved family satisfaction and quality of life, improved use of healthcare resources, and longer survival. Palliative care is one of the fastest growing areas of health care in the US, and it’s changing as new treatments emerge, especially for cancer patients.

Over the last decade, ACS-funded researchers led the field in publishing studies on the benefits of early palliative care , finding that patients with metastatic non-small-cell lung cancer who received palliative care early in their treatment had big improvements in their quality of life and mood. A 2017 paper by an ACS-grantee explained why the US needs more palliative care programs, outlining ideas for implementing a national strategy . Furthermore, ACS grantees helped develop an online and face-to-face curriculum to increase education about pediatric palliative care for healthcare providers and to promote resilience as part of stress management for parents of children living with a serious illness.

ACS has taken steps to prepare for the next decade of cancer research including developing a blueprint to improve cancer control in the US, increasing the ability for some of the best cancer experts to work together , collecting blood and tissue samples from volunteers in the ACS Cancer Prevention Studies-3 (CPS-3) that will allow for more research, and starting new partnerships that can help promote more cancer research, such as with St. Baldrick’s Foundation for children’s cancers and the Melanoma Research Alliance. Just as researchers build on past discoveries while keeping their eyes on the future, our eyes are on our competitor—cancer—and on the prize—a world without cancer.

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What Makes the Nobel-Winning Breakthroughs in Immunotherapy So Revolutionary

Targeting the immune system to fight cancer could be the first step to defeating the disease

Duane Mitchell The Conversation

There are moments in the history of scientific achievement that benchmark the end of an era and the beginning of a new phase of reality for mankind.

The significance of these inflection points is sometimes readily apparent. NASA astronaut Neil Armstrong’s first step onto the surface of the moon on July 20, 1969, marked a new phase of space exploration. Other advances take many years for the historical significance to manifest, with an impact that appreciates over decades. That was the case with the development of the mechanized clock of the 15th century and the invention of the telephone in 1876.

Attempts to rid people of their cancer burden date back to 1600 B.C. when the disease was first recognized. But the idea of using a patient’s own immune system to eliminate aggressive cancers is more recent. Nobel laureate Paul Ehrlich first postulated that the immune system might control tumors more than 120 years ago. Since then, researchers have tried to boost the immune system to wipe out cancers.

This week, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for discoveries that have led to new medicines that activate the immune system and drive it to fight cancers. These therapies can defeat even the deadliest malignancies.

Allison and Honjo have revolutionized our understanding of how the immune system recognizes tumor cells and have created a paradigm shift in clinical oncology that will likely alter how we treat cancer for the foreseeable future.

Standard weapons for fighting cancer

To date, our best tools for treating aggressive cancers that have spread beyond the range of curative surgery have been radiation therapy and systemic chemotherapy agents.

For the most part these treatments kill rapidly dividing tumor cells by damaging their DNA or disrupting other essential cellular processes. This has led to most of the significant treatment advances we have achieved in terms of long-term survival in patients with advanced cancers.

I believe that soon cancer immunotherapy will equal, or rival, the impact of radiation and chemotherapy for patients diagnosed with cancer.

To understand the significance of Allison and Honjo’s discoveries, one must appreciate researchers have been trying to rally a powerful immune response against tumor cells for the past century. Prior to Allison and Honjo’s work, researchers believed that aggressive cancers grew unchecked because the immune response was too weak. The consensus was that if one could stimulate the immune system, it would respond and destroy the invasive tumor cells.

Immune checkpoints

Allison and Honjo, however, made a critical leap when they characterized two very important and potent pathways – called “immune checkpoints” – that can shut down the immune response. These pathways inhibit T cells – white blood cells that are charged with destroying virus-infected cells and tumor cells – and prevent them from “seeing” and attacking the tumor.

Allison and Honjo identified and characterized two different proteins, called CTLA-4 and PD-1, respectively, that sit on the surface of T-cells. When these proteins interact with matching proteins on tumor cells or other immune cells – the way a key fits a lock – the T-cells fall into “sleep mode” and don’t attack the tumor.

In many patients with cancer, these CTLA-4 and PD-1 pathways shut down anti-tumor immune activity. Without immune surveillance, the tumors grow and spread. This meant that our early attempts to activate the immune system were like trying to drive a car with the brake pedal pressed to the floor. No matter how we tried, or stepped on the gas, the brakes thwarted any progress.

But Allison and Honjo’s research led to the development of a new type of drug: monoclonal antibodies that block the regulatory pathways controlled by CTLA-4 and PD-1. These drugs, called immune checkpoint inhibitors , basically attach to the CTLA-4 and PD-1 proteins and prevent them from switching off the T-cells. These new antibody-drugs have led to dramatic tumor regressions. The results are so impressive that the FDA has approved their use for a variety of advanced cancers such as: metastatic melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancers, and other tumors.

A new arsenal of checkpoint inhibitor drugs

The excitement surrounding cancer immunotherapy is due, in no small part, to the fact that these new medicines are revolutionizing how we treat advanced malignancies in which chemotherapy, surgery and radiation have failed. Furthermore, cancer immunotherapy has already become the preferred first option treatment for some cases of metastastic melanoma , the deadliest form of skin cancer. It is currently being evaluated as the first line option over traditional chemotherapy in other cancers.

CTLA-4 and PD-1 represent only the first two well-characterized immune checkpoints among an expanding list of targets that have been identified on immune cells and are believed important for modulating T-cell tumor fighting.

There are more than a dozen immune checkpoint inhibitors that have already entered clinical development and there are endless possibilities for combining these new inhibitors with those that have already been shown to improve clinical responses in treated patients.

The risks of unleashing the immune system

Although immune therapy is a breakthrough, it is not without risks to the patient. Taking the brakes off of the immune system can trigger undesirable and in some cases deadly consequences for patients treated with drugs. The killing power of the immune system is tightly regulated to protect normal cells from attacks that can damage critical tissues. Removing the brakes with immune checkpoint inhibitors can cause damaging inflammation in the skin, gut, heart, lungs and other vital organs. These risks can add up when these potent inhibitors are combined. And, the long-term side effects of immune checkpoint inhibition are not fully understood.

While the clinical responses to these treatments can be dramatic, long-term tumor regressions are achieved only in a minority (usually less than 20 to 30 percent depending on the tumor type) of treated patients. Also, the use of the PD-1 and CTLA-4 checkpoint inhibitors has not proven effective against all tumor types. In our own studies of malignant brain tumors, my colleagues and I have identified unique properties that make them resistant to immunotherapy and have begun to identify strategies for overcoming this treatment resistance.

Thus, we have much still to learn and significant room for improvement in order to maximize the benefits of immunotherapy for all patients. Nonetheless, we have definitively entered a new era of clinical medicine with an accelerated progress in oncology treatments.

More than one in three individuals will be diagnosed with cancer during their lifetime. Despite our continued advances in cancer prevention and early detection, a significant proportion of these individuals will be faced with advanced disease. With continued rapid progress building on Allison’s and Honjo’s pioneering discoveries, it is increasingly likely that a patient’s own immune system will prove the most effective strategy and final defense against an advancing and relentless malignancy.

Duane Mitchell, Professor of Neurosurgery, University of Florida

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Harvard study, almost 80 years old, has proved that embracing community helps us live longer, and be happier

Part of the tackling issues of aging series.

A series on how Harvard researchers are tackling the problematic issues of aging.

W hen scientists began tracking the health of 268 Harvard sophomores in 1938 during the Great Depression, they hoped the longitudinal study would reveal clues to leading healthy and happy lives.

They got more than they wanted.

After following the surviving Crimson men for nearly 80 years as part of the Harvard Study of Adult Development , one of the world’s longest studies of adult life, researchers have collected a cornucopia of data on their physical and mental health.

Of the original Harvard cohort recruited as part of the Grant Study, only 19 are still alive, all in their mid-90s. Among the original recruits were eventual President John F. Kennedy and longtime Washington Post editor Ben Bradlee. (Women weren’t in the original study because the College was still all male.)

In addition, scientists eventually expanded their research to include the men’s offspring, who now number 1,300 and are in their 50s and 60s, to find out how early-life experiences affect health and aging over time. Some participants went on to become successful businessmen, doctors, lawyers, and others ended up as schizophrenics or alcoholics, but not on inevitable tracks.

“Loneliness kills. It’s as powerful as smoking or alcoholism.” Robert Waldinger, psychiatrist, Massachusetts General Hospital

During the intervening decades, the control groups have expanded. In the 1970s, 456 Boston inner-city residents were enlisted as part of the Glueck Study, and 40 of them are still alive. More than a decade ago, researchers began including wives in the Grant and Glueck studies.

Over the years, researchers have studied the participants’ health trajectories and their broader lives, including their triumphs and failures in careers and marriage, and the finding have produced startling lessons, and not only for the researchers.

“The surprising finding is that our relationships and how happy we are in our relationships has a powerful influence on our health,” said Robert Waldinger , director of the study, a psychiatrist at Massachusetts General Hospital and a professor of psychiatry at Harvard Medical School . “Taking care of your body is important, but tending to your relationships is a form of self-care too. That, I think, is the revelation.”

Close relationships, more than money or fame, are what keep people happy throughout their lives, the study revealed. Those ties protect people from life’s discontents, help to delay mental and physical decline, and are better predictors of long and happy lives than social class, IQ, or even genes. That finding proved true across the board among both the Harvard men and the inner-city participants.

“The people who were the most satisfied in their relationships at age 50 were the healthiest at age 80,” said Robert Waldinger with his wife Jennifer Stone.

Rose Lincoln/Harvard Staff Photographer

The long-term research has received funding from private foundations, but has been financed largely by grants from the National Institutes of Health, first through the National Institute of Mental Health, and more recently through the National Institute on Aging.

Researchers who have pored through data, including vast medical records and hundreds of in-person interviews and questionnaires, found a strong correlation between men’s flourishing lives and their relationships with family, friends, and community. Several studies found that people’s level of satisfaction with their relationships at age 50 was a better predictor of physical health than their cholesterol levels were.

“When we gathered together everything we knew about them about at age 50, it wasn’t their middle-age cholesterol levels that predicted how they were going to grow old,” said Waldinger in a popular TED Talk . “It was how satisfied they were in their relationships. The people who were the most satisfied in their relationships at age 50 were the healthiest at age 80.”

He recorded his TED talk, titled “What Makes a Good Life? Lessons from the Longest Study on Happiness,” in 2015, and it has been viewed 13,000,000 times.

The researchers also found that marital satisfaction has a protective effect on people’s mental health. Part of a study found that people who had happy marriages in their 80s reported that their moods didn’t suffer even on the days when they had more physical pain. Those who had unhappy marriages felt both more emotional and physical pain.

Those who kept warm relationships got to live longer and happier, said Waldinger, and the loners often died earlier. “Loneliness kills,” he said. “It’s as powerful as smoking or alcoholism.”

According to the study, those who lived longer and enjoyed sound health avoided smoking and alcohol in excess. Researchers also found that those with strong social support experienced less mental deterioration as they aged.

In part of a recent study , researchers found that women who felt securely attached to their partners were less depressed and more happy in their relationships two-and-a-half years later, and also had better memory functions than those with frequent marital conflicts.

“When the study began, nobody cared about empathy or attachment. But the key to healthy aging is relationships, relationships, relationships.” George Vaillant, psychiatrist

“Good relationships don’t just protect our bodies; they protect our brains,” said Waldinger in his TED talk. “And those good relationships, they don’t have to be smooth all the time. Some of our octogenarian couples could bicker with each other day in and day out, but as long as they felt that they could really count on the other when the going got tough, those arguments didn’t take a toll on their memories.”

Since aging starts at birth, people should start taking care of themselves at every stage of life, the researchers say.

“Aging is a continuous process,” Waldinger said. “You can see how people can start to differ in their health trajectory in their 30s, so that by taking good care of yourself early in life you can set yourself on a better course for aging. The best advice I can give is ‘Take care of your body as though you were going to need it for 100 years,’ because you might.”

The study, like its remaining original subjects, has had a long life, spanning four directors, whose tenures reflected their medical interests and views of the time.

Under the first director, Clark Heath, who stayed from 1938 until 1954, the study mirrored the era’s dominant view of genetics and biological determinism. Early researchers believed that physical constitution, intellectual ability, and personality traits determined adult development. They made detailed anthropometric measurements of skulls, brow bridges, and moles, wrote in-depth notes on the functioning of major organs, examined brain activity through electroencephalograms, and even analyzed the men’s handwriting.

Now, researchers draw men’s blood for DNA testing and put them into MRI scanners to examine organs and tissues in their bodies, procedures that would have sounded like science fiction back in 1938. In that sense, the study itself represents a history of the changes that life brings.

6 factors predicting healthy aging According to George Vaillant’s book “Aging Well,” from observations of Harvard men in long-term aging study

Physically active.

Absence of alcohol abuse and smoking

Having mature mechanisms to cope with life’s ups and downs

Healthy weight

Stable marriage.

Psychiatrist George Vaillant, who joined the team as a researcher in 1966, led the study from 1972 until 2004. Trained as a psychoanalyst, Vaillant emphasized the role of relationships, and came to recognize the crucial role they played in people living long and pleasant lives.

In a book called “Aging Well,” Vaillant wrote that six factors predicted healthy aging for the Harvard men: physical activity, absence of alcohol abuse and smoking, having mature mechanisms to cope with life’s ups and downs, and enjoying both a healthy weight and a stable marriage. For the inner-city men, education was an additional factor. “The more education the inner city men obtained,” wrote Vaillant, “the more likely they were to stop smoking, eat sensibly, and use alcohol in moderation.”

Vaillant’s research highlighted the role of these protective factors in healthy aging. The more factors the subjects had in place, the better the odds they had for longer, happier lives.

“When the study began, nobody cared about empathy or attachment,” said Vaillant. “But the key to healthy aging is relationships, relationships, relationships.”

“We want to find out how it is that a difficult childhood reaches across decades to break down the body in middle age and later.” Robert Waldinger

The study showed that the role of genetics and long-lived ancestors proved less important to longevity than the level of satisfaction with relationships in midlife, now recognized as a good predictor of healthy aging. The research also debunked the idea that people’s personalities “set like plaster” by age 30 and cannot be changed.

“Those who were clearly train wrecks when they were in their 20s or 25s turned out to be wonderful octogenarians,” he said. “On the other hand, alcoholism and major depression could take people who started life as stars and leave them at the end of their lives as train wrecks.”

The study’s fourth director, Waldinger has expanded research to the wives and children of the original men. That is the second-generation study, and Waldinger hopes to expand it into the third and fourth generations. “It will probably never be replicated,” he said of the lengthy research, adding that there is yet more to learn.

“We’re trying to see how people manage stress, whether their bodies are in a sort of chronic ‘fight or flight’ mode,” Waldinger said. “We want to find out how it is that a difficult childhood reaches across decades to break down the body in middle age and later.”

Lara Tang ’18, a human and evolutionary biology concentrator who recently joined the team as a research assistant, relishes the opportunity to help find some of those answers. She joined the effort after coming across Waldinger’s TED talk in one of her classes.

“That motivated me to do more research on adult development,” said Tang. “I want to see how childhood experiences affect developments of physical health, mental health, and happiness later in life.”

Asked what lessons he has learned from the study, Waldinger, who is a Zen priest, said he practices meditation daily and invests time and energy in his relationships, more than before.

“It’s easy to get isolated, to get caught up in work and not remembering, ‘Oh, I haven’t seen these friends in a long time,’ ” Waldinger said. “So I try to pay more attention to my relationships than I used to.”

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