Findings About Dostarlimab, A New Antibody Drug, Very Encouraging, Says Expert In Cancer Treatment

According to New York Times, in a small clinical trial, 18 patients took a drug called Dostarlimab for around six months, and in the end, every one of them saw their tumours disappear. The findings concerning dostarlimab, an antibody drug, in experimental treatment of rectal cancer patients is very encouraging but there is need for long-term studies to understand the real impact, an expert in cancer treatment has said.

“This new trial at MSKCC in a small number of patients, with locally advanced rectal cancer patients who had MMR (MisMatch repair) deficiency, have shown total disappearance of tumour without any additional treatment in all 100 percent of them. This is very encouraging but we must note that long term studies are required to understand the real impact,” Dr. (Col.) R. Ranga Rao, Chairman, Oncology, of Paras Hospitals in Gurugram said.

“The drug is still investigational and the trial is limited to patients of a specific type , that constitute about 4 to 5 per cent of rectal cancers. While this is highly encouraging, we must not prematurely jump to conclusions that we have found a cure for all cancers, all stages, and no chemotherapy, surgery is ever required,” he added.

He said it is well recognized that Immunotherapy with PDL 1 blockers in MMRd patients is effective. “Already immunotherapy has made a big difference in the field of cancer of all types. Several earlier trials have shown encouraging responses,” Dr Rao said.

In what appears to be a miracle and ‘first time in history’, a small clinical trial has found that every single rectal cancer patient who received an experimental treatment found that their cancer had vanished.

According to New York Times, in the small clinical trial conducted by Memorial Sloan Kettering Cancer Center, 18 patients took a drug called Dostarlimab for around six months, and in the end, every one of them saw their tumours disappear. Dr Luis A. Diaz J. of New York’s Memorial Sloan Kettering Cancer Center (MSKCC) said this was “the first time this has happened in the history of cancer”.

According to experts, Dostarlimab is a drug with laboratory-produced molecules and it acts as substitute antibodies in the human body. The cancer is undetectable by physical exam; endoscopy; positron emission tomography or PET scans or MRI scans, added Experts. This proves that Dostarlimab can be a ‘potential’ cure for one of the most deadly common cancers.

According to New York Times, patients involved in the clinical trial earlier underwent treatments such as chemotherapy, radiation, and invasive surgery that could result in bowel, urinary, and even sexual dysfunction. The 18 patients went into the trial expecting to have to go through these procedures as the next step. However, to their surprise, no further treatment was needed.

The findings of this trial have shocked experts and they have pointed out that complete remission in every single patient is “unheard-of”. Dr Alan P. Venook, who is a colorectal cancer specialist at the University of California, said that the complete remission in every single patient is “unheard-of”. He hailed the research as a “world-first”. Experts stated that the research was impressive as not all of the patients suffered significant complications from the drug trial.

Critics:

Tesaro, a biotech company based out of Massachusetts developed the drug. Tesaro was acquired by GlaxoSmithKline in 2019, dostarlimab is also known by the brand name Jemparli. Dostarlimab was developed to treat women with recurrent or advanced endometrial cancer.

On August 17, 2021, the FDA approved dostarlimab-gxly (brand name Jemperli) for adult patients with mismatch repair-deficient recurrent or advanced solid tumours, as determined by an FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.

Rectal cancer remission

According to reports, 18 patients in the clinical trial took Dostarlimab for around six months and after over 12 months the doctors found that their cancer disappeared. While it’s a small trial so far, the results have been impressive; they were published in The New England Journal of Medicine and featured at the nation’s largest gathering of clinical oncologists in June 2022.


In every case, rectal cancer disappeared after immunotherapy — without the need for the standard treatments of radiation, surgery, or chemotherapy — and cancer has not returned in any of the patients, who have been cancer-free for up to two years.

It’s incredibly rewarding to get these happy tears and happy emails from the patients in this study who finish treatment and realise, ‘Oh my God, I get to keep all my normal body functions that I feared I might lose to radiation or surgery,’ expressed Dr Andrea Cercek, Medical Oncologist, Memorial Sloan Kettering Cancer Center (MSK).

Dr Cercek added, “The most exciting part of this is that every single one of our patients has only needed immunotherapy. We haven’t radiated anybody, and we haven’t put anybody through surgery.” She continued, “They have preserved normal bowel function, bladder function, sexual function, fertility. Women have their uterus and ovaries. It’s remarkable.”

This clinical trial could pave the way for treating other forms of cancer in the future. As the trial continues at MSK, Dr Luis Alberto Diaz, Medical Oncologist, Memorial Sloan Kettering Cancer Center (MSK) said, “It’s the tip of the iceberg.” He explains, “We are investigating if this same method may help other cancers where the treatments are often life-altering and tumours can be MMRd. We are currently enrolling patients with gastric (stomach), prostate, and pancreatic cancers.”

Dostarlimab clinical trial reception by the Indian medical community

Since the trial results have been published, it has created a lot of buzz and has got the entire medical community discussing how it could pave the path for future treatment for various cancers, ETHealthWorld spoke to few experts on the drug trial. Commenting on the trial, “It is definitely a big step towards efficient cancer care. The preliminary data on Dostarlimab PD1 monotherapy has been very encouraging in high-risk rectal cancer patients and has been recently presented at the ASCO meeting in Chicago and subsequently published in NEJM.

We would definitely need further studies on larger groups of patients across the globe to establish it as a standard of care for rectal cancer. Trials are also being conducted to study its effectiveness for cervical cancer, and endometrial cancer amongst others,” said Dr Pankaj Kumar Panda, Senior Research Officer, Apollo Proton Cancer Centre.

Source: Findings about Dostarlimab, a new antibody drug, very encouraging, says expert in cancer treatment

More contents:

3 Things To Ask Your Doctor About Breast Cancer Treatment

As far as illnesses go, breast cancer is a relatively common one: 13 percent of women in the United States will develop breast cancer over their lifetime, according to the National Cancer Institute. That works out to one in eight women, so if you know more than eight women, odds are you probably know someone who has had or will be diagnosed with breast cancer in the future.

And if you’re trying to understand your risk of developing breast cancer or if you or a loved one are facing a diagnosis, that means one thing: You probably have questions for a doctor.

To help you assemble your list, we asked Virginia Kaklamani, MD, leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center, for her advice on what to ask. According to Dr. Kaklamani, there are a few important things to keep in mind as you’re crafting your questions, such as your family history, lifestyle risk factors, and available treatment options.

On the treatment front, Dr. Kaklamani says one of the misconceptions she hears most often is that breast cancer treatment always involves chemotherapy and is very toxic. In response, she reminds people how far treatment options—and the tools we have to determine which treatment may work best for each individual person—have come in the past 20 years.

Case in point: Just last year, a landmark study published in The New England Journal of Medicine showed that, thanks to a genomic test called the Oncotype DX Breast Recurrence Score® test, even more patients with a common type of early-stage breast cancer may be spared chemotherapy than previously thought, including those who are traditionally considered higher-risk due to their cancer spreading to at least one lymph node.

That means more treatment plans tailored to each individual patient, and less of a chance of overprescribing chemo to those who may not benefit from it.

Learning something already? With education in mind, we asked Dr. Kaklamani to share her insights on questions you should ask your doctor about breast cancer—whether you’re trying to stay on top of your health, or you’re exploring your breast cancer treatment options.

What role does race play in breast cancer?

There are many factors that contribute to breast cancer risk, including age, family history, alcohol consumption, obesity, and race. White women are most likely to develop breast cancer, Dr. Kaklamani says, though Black women are more likely to die from it (40 percent more likely, according to the Centers for Disease Control and Prevention).

Studies have shown that Black women have a higher risk of being diagnosed with later stages of disease,” Dr. Kaklamani says. “So instead of coming in with stage one or stage two, they might come in with stage two or three or even stage four breast cancer. It’s been very hard to understand why.

Most of the data suggests that it’s related both to the type of breast cancer that they get (because they get more triple negative breast cancer—that’s more aggressive, so we tend to find it later), but also to socioeconomic factors.”

By asking your doctor to discuss the connections between race and breast cancer with you, you’ll be able to more openly advocate for yourself and properly assess your personal risk factors.

What types of tests are available to provide insight about a breast cancer treatment plan?

If you have breast cancer, you should definitely ask your doctor for a thorough rundown on your treatment options, Dr. Kaklamani says, starting with the types of tests available to help craft your individual treatment plan.

Genomic tests—like the Oncotype DX® test—look at the specific genes in a tumor to see whether they are over- or under-active. For people diagnosed with early-stage invasive breast cancer (HR-positive and HER2-negative with or without involvement of the lymph nodes), the Oncotype DX Breast Recurrence Score® result tells patients and their doctors not only how aggressive their cancer is and the risk of it returning, but more importantly, whether chemotherapy might be a beneficial treatment option or if it can be safely omitted, Dr. Kaklamani says.

“The good thing about the [result that you get from the Oncotype® test] is that it’s specific to the woman that we are testing,” she says. “All of these clinical trials that we’ve done have included thousands and thousands of women, [but] none of those women are present in my office when I talk to that specific person about their breast cancer. [Each test result] represents that woman’s breast cancer.”

Personalized is obviously better when it comes to something as delicate as cancer treatment (you wouldn’t take someone else’s prescription medicine, would you?), so asking your doctor about genomic testing can help ensure you’re getting a treatment plan that’s properly tailored to your needs.

Should I be doing a self breast exam?

In 2015, the American Cancer Society stopped recommending that people perform their own breast exams, but that doesn’t mean you’re off the hook for keeping tabs on your breast health, Dr. Kaklamani says.

“The guidelines are very clear that there has to be what they call ‘breast self awareness,'” she says. “This is extremely important to be aware of what your breasts look like, and if you do notice something that has changed, that you see your physician immediately.”

Dr. Kaklmani notes that one study showed that nurses who were taught how to properly perform self breast exams were able to accurately detect their breast cancer—demonstrating that if people are properly trained, self breast exams can be effective. That training should fall on gynecologists and primary care physicians, she says, so ask yours for instructions during your next visit.

By: Dr. Kaklamani Paid consultant for Exact Sciences Corporation.

Source: 3 Things To Ask Your Doctor About Breast Cancer Treatment | Well+Good

.

Related contents:

Stool Tests Might Help Spot Early Pancreatic Cancer

Stool tests might provide a useful way to help doctors spot early pancreatic cancer, say researchers.

They have been trialling the concept in a study with 136 volunteers.

The findings, described in the journal Gut, suggest detectable changes involving gut bugs could provide a warning sign that a tumour is present.

Pancreatic cancer often doesn’t cause symptoms in the early stages. That means it is usually more advanced and harder to treat when it is found.

As the cancer grows it may cause vague symptoms, such as indigestion, changes to bowel habit and some tummy or back pain. Some people see their GP several times before being diagnosed.

Currently, fewer than one in 20 of those with the most common form – ductal adenocarcinoma – will survive for five years or more. Earlier detection could improve those odds.

The Spanish team behind the work recruited patients from two hospitals – one in Madrid and the other in Barcelona. Only some of the patients had pancreatic ductal adenocarcinoma, while the others were selected as controls for comparison.

The researchers collected and analysed spit and stool samples from the volunteers to see if there was any discernible difference between the groups.

While the saliva samples drew a blank, the stool ones did show a difference that the team believe could be useful for helping to diagnose pancreatic cancer.

It was a distinct pattern or genomic profile of gut bacteria, fungi and other microbes.

This consistently identified patients with the disease, irrespective of how far it had progressed, suggesting that characteristic microbiome signatures emerge early on and that the stool microbiome might pick up early stage disease, say the researchers.

They recommend more studies – and some are already taking place.

Independent researchers in Germany have validated the findings in a small number of patients, and the test is also being trialled in Japan.

Source: Stool tests might help spot early pancreatic cancer – BBC News

.

Critics: By: Samuel Lovett

Stool samples could soon be analyzed to help detect pancreatic cancer after scientists identified microorganisms that appear to place individuals at greater risk of developing the illness. In a study of 136 people, scientists found that 27 different microbes were abundant in the stool samples of those diagnosed with the most common form of pancreatic cancer.

This “microbial profile” consistently identified patients with the disease, irrespective of how far it had progressed, raising hope that a new screening test could be developed to diagnose pancreatic cancer.

Pancreatic cancer is deadly and can be very difficult to treat, with only around one in four people surviving one year or more after diagnosis. Dr Helen Rippon, chief executive of Worldwide Cancer Research, which helped fund the study, said: “This new breakthrough builds on the growing evidence that the microbiome – the collection of microorganisms that live side by side with the cells inside our body – is linked to the development of cancer.

References

“Can pancreatic cancer be prevented?”. American Cancer Society. 11 June 2014. Archived from the original on 13 November 2014. Retrieved 13 November 2014.

Cancer Without Chemotherapy A Totally Different World

Dr. Seema Doshi was shocked and terrified when she found a lump in her breast that was eventually confirmed to be cancerous. “That rocked my world,” said Dr. Doshi, a dermatologist in private practice in the Boston suburb of Franklin who was 46 at the time of her diagnosis. “I thought, ‘That’s it. I will have to do chemotherapy.’”

She was wrong.

Dr. Doshi was the beneficiary of a quiet revolution in breast cancer treatment, a slow chipping away at the number of people for whom chemotherapy is recommended. Chemotherapy for decades was considered “the rule, the dogma,” for treating breast cancer and other cancers, said Dr. Gabriel Hortobagyi, a breast cancer specialist at MD Anderson Cancer Center in Houston. But data from a variety of sources offers some confirmation of what many oncologists say anecdotally — the method is on the wane for many cancer patients.

Genetic tests can now reveal whether chemotherapy would be beneficial. For many there are better options with an ever-expanding array of drugs, including estrogen blockers and drugs that destroy cancers by attacking specific proteins on the surface of tumors. And there is a growing willingness among oncologists to scale back unhelpful treatments.

The result spares thousands each year from the dreaded chemotherapy treatment, with its accompanying hair loss, nausea, fatigue, and potential to cause permanent damage to the heart and to nerves in the hands and feet.

The diminution of chemotherapy treatment is happening for some other cancers, too, including lung cancer, the most common cause of cancer deaths among men and women in the United States, killing about 132,000 Americans each year. Breast cancer is the second leading cause of cancer deaths among women, killing 43,000.

Still, the opportunity to avoid chemotherapy is not evenly distributed, and is often dependent on where the person is treated and by whom.

But for some patients who are lucky enough to visit certain cancer treatment centers, the course of therapy has changed. Now, even when chemotherapy is indicated, doctors often give fewer drugs for less time.

“It’s a totally different world,” said Dr. Lisa Carey, a breast cancer specialist at the University of North Carolina.

Dr. Robert Vonderheide, a lung cancer specialist who heads the University of Pennsylvania’s Abramson Cancer Center, remembers his early days on the job, about 20 years ago.

“The big discussion was, Do you give patients two different types of chemotherapy or three?” he said. There was even a clinical trial to see whether four types of chemotherapy would be better.

“Now we are walking in to see even patients with advanced lung cancer and telling them, ‘No chemo,’” Dr. Vonderheide said.

The breast cancer treatment guidelines issued by the National Cancer Institute 30 years ago were harsh: chemotherapy for about 95 percent of patients with breast cancer.

The change began 15 years ago, when the first targeted drug for breast cancer, Herceptin, was approved as an initial treatment for about 30 percent of patients who have a particular protein on their tumor surface. It was given with chemotherapy and reduced the chance of a recurrence by half and the risk of dying from breast cancer by a third, “almost regardless of how much and what type of chemotherapy was used,” Dr. Hortobagyi said.

In a few studies, Herceptin and another targeted drug were even given without chemotherapy, and provided substantial benefit, he added.

That, Dr. Hortobagyi said, “started to break the dogma” that chemotherapy was essential. But changing cancer therapies was not easy. “It is very scary,” to give fewer drugs, Dr. Hortobagyi said.

“It is so much easier to pile on treatment on top of treatment,” he continued, “with the promise that ‘if we add this it might improve your outcome.’”

But as years went by, more and more oncologists came around, encouraged by new research and new drugs.

The change in chemotherapy use is reflected in a variety of data collected over the years. A study of nearly 3,000 women treated from 2013 to 2015 found that in those years, chemotherapy use in early-stage breast cancer declined to 14 percent, from 26 percent. For those with evidence of cancer in their lymph nodes, chemotherapy was used in 64 percent of patients, down from 81 percent.

More recent data, compiled by Dr. Jeanne Mandelblatt, a professor of medicine and oncology at Georgetown, and her colleagues, but not yet published, included 572 women who were 60 or older and enrolled in a federal study at 13 medical centers. Overall, 35 percent of older women received chemotherapy in 2012. That number fell to 19 percent by the end of 2019.

Cheaper and faster genetic sequencing has played an important role in this change. The technology made it easier for doctors to test tumors to see if they would respond to targeted drugs. Genetic tests that looked at arrays of proteins on cancer cells accurately predicted who would benefit from chemotherapy and who would not.

There are now at least 14 new targeted breast cancer drugs on the market — three were approved just last year — with dozens more in clinical trials and hundreds in initial development.

Some patients have reaped benefits beyond avoiding chemotherapy. The median survival for women with metastatic breast cancer who are eligible for Herceptin went from 20 months in the early 1990s, to about 57 months now, with further improvements expected as new drugs become available. For women with tumors that are fed by estrogen, the median survival increased from about 24 months in the 1970s to almost 64 months today.

Now some are in remission 10 or even 15 years after their initial treatment, Dr. Hortobagyi said.

“At breast cancer meetings, a light bulb went off. ‘Hey, maybe we are curing these patients,’” Dr. Hortobagyi said.

Dr. Doshi’s oncologist, Dr. Eric Winer of the Dana-Farber Cancer Institute, gave her good news: A genetic test of her tumor indicated she would not get any significant benefit from chemotherapy. Hormonal therapy to deprive her cancer of the estrogen that fed it would suffice.

But as much as Dr. Doshi dreaded chemotherapy, she worried about forgoing it. What if her cancer recurred? Would chemotherapy, awful as it is, improve her outcome?

She got a second opinion.

The doctor she consulted advised a “very aggressive” treatment, Dr. Doshi said — a full lymph node dissection followed by chemotherapy.

She had multiple conversations with Dr. Winer, who ended up discussing her case with four other specialists, all of whom recommended against chemotherapy.

Finally, Dr. Doshi said, “my husband said I should just pick a horse and run with it.” She trusted Dr. Winer.

Her struggles mirror what oncologists themselves go through. It can take courage to back off from chemotherapy.

One of the most difficult situations, Dr. Winer said, is when a patient has far more advanced disease than Dr. Doshi did — hers had spread to three lymph nodes but no further — and is not a candidate for one of the targeted treatments. If such a patient has already had several types of chemotherapy, more is unlikely to help. That means there is no treatment.

It falls to Dr. Winer to tell the patient the devastating news.

Dr. Susan Domchek, a breast cancer specialist at the University of Pennsylvania, can relate to those struggles.

“It is the nature of being an oncologist to be perpetually worried that you are either overtreating or undertreating a patient,” she said.

“Some cases keep me up at night,” she said, “specifically the cases where the risks and benefits of chemotherapy are close, yet the stakes still feel so high.”

When Dr. Roy Herbst of Yale started in oncology about 25 years ago, nearly every lung cancer patient with advanced disease got chemotherapy.

With chemotherapy, he said, “patients would be sure to have one thing: side effects.” Yet despite treatment, most tumors continued to grow and spread. Less than half his patients would be alive a year later. The five-year survival rate was just 5 to 10 percent.

Those dismal statistics barely budged until 2010, when targeted therapies began to emerge. There are now nine such drugs for lung cancer patients, three of which were approved since May of this year. About a quarter of lung cancer patients can be treated with these drugs alone, and more than half who began treatment with a targeted drug five years ago are still alive. The five-year survival rate for patients with advanced lung cancer is now approaching 30 percent.

But the drugs eventually stop working for most, said Dr. Bruce Johnson, a lung cancer specialist at Dana-Farber. At that point many start on chemotherapy, the only option left.

Another type of lung cancer treatment was developed about five years ago — immunotherapy, which uses drugs to help the immune system attack cancer. Two-thirds of patients from an unpublished study at Dana-Farber were not eligible for targeted therapies but half of them were eligible for immunotherapy alone, and others get it along with chemotherapy.

Immunotherapy is given for two years. With it, life expectancy has almost doubled, said Dr. Charu Aggarwal, a lung cancer specialist at the University of Pennsylvania.

Now, said Dr. David Jackman of Dana-Farber, chemotherapy as the sole initial treatment for lung cancer, is shrinking, at least at that cancer treatment center, which is at the forefront of research. When he examined data from his medical center he found that, since 2019, only about 12 percent of patients at Dana-Farber got chemotherapy alone, Dr. Jackman said. Another 21 percent had a targeted therapy as their initial treatment, and among the remaining patients, 85 percent received immunotherapy alone or with chemotherapy.

In contrast, in 2015, only 39 out of 239 patients received a targeted therapy as their initial treatment. The rest got chemotherapy.

Dr. Aggarwal said she was starting to witness something surprising — some who had received immunotherapy are still alive, doing well, and have no sign of cancer five years or more after their initial treatment.

She said: “I started out saying to patients, ‘I will treat you with palliative intent. This is not curative.’”

Now some of those same patients are sitting in her clinic wondering if their disease is gone for good.

Chong H. Hammond’s symptoms were ambiguous — a loss of appetite and her weight had dropped to 92 pounds.

“I did not want to look at myself in the mirror,” she said.

It took from October 2020 until this March before doctors figured it out. She had metastatic lung cancer.

Then Dr. Timothy Burns, a lung cancer specialist at the University of Pittsburgh, discovered that Mrs. Hammond, who is 71 and lives in Gibsonia, Pa., had a tumor with two unusual mutations.

Although a drug for patients with Mrs. Hammond’s mutations has not been tested, Dr. Burns is an investigator in a clinical trial involving patients like her.

He offered her the drug osimertinib, which is given as a pill. This allowed her to avoid chemotherapy.

Ten days later she began feeling better and started eating again. She had energy to take walks. She was no longer out of breath.

Dr. Burns said her lung tumors are mostly gone and tumors elsewhere have shrunk.

If Mrs. Hammond had gotten chemotherapy, her life expectancy would be a year or a little more, Dr. Burns said. Now, with the drug, it is 38.6 months.

Dr. Burns is amazed by how lung cancer treatment has changed.

“It’s been remarkable,” he said. “We still quote the one-year survival but now we are talking about survival for two, three, four or even five years. I even have patients on the first targeted drugs that are on them for six or even seven years.”

Mark Catlin, who is being treated at Dana-Farber, is one of those patients.

On March 8, 2014, Mr. Catlin, who has never smoked, noticed a baseball-size lump under his arm. “The doctors told me to hope for anything but lung,” he said.

But lung it was. It had already spread under his arm and elsewhere.

Oncologists in Appleton, Wis., where he lives, wanted to start chemotherapy.

“I was not a fan,” Mr. Catlin said. His son, who lives in the Boston area, suggested he go to Dana-Farber.

There, he was told he could take a targeted therapy but that it would most likely stop working after a couple of years. He is 70 now, and still taking the therapy seven years later — two pills a day, with no side effects.

He rides a bike 15 to 25 miles every day or runs four to five miles. His drug, crizotinib, made by Pfizer, has a list price of $20,000 a month. Mr. Catlin’s co-payment is $1,000 a month. But, he says, “it’s keeping me alive.” “It’s almost surreal,” Mr. Catlin said.

Gina Kolata

By:

Source: Cancer Without Chemotherapy: ‘A Totally Different World’ – The New York Times

.

Related Contents:

The Cancer Custodians Hidden Truths

woman-with-headscarf-getting-chemo-treatment-article

Part of Dennis Plenker’s daily job is growing cancer. And a variety of different ones, too. Depending on the day and the project, different tumors may burgeon in the petri dishes stocked in the Cold Spring Harbor Laboratory where Plenker works as a research investigator. They might be aggressive breast cancers.

They might be glioblastomas, one of the deadliest brain tumors that rob patients of their ability to speak or read as they crowd out normal cells. Or they might be pancreatic cancers, the fast and vicious slayers that can overtake a healthy person within weeks or even days.

These tiny tumor chunks are transparent and bland—they look like little droplets of hair gel that accidentally plopped into a plastic dish and took hold. But their unassuming appearance is deceptive. If they were still in the human bodies they came from, they would be sucking up nutrients, rapidly growing and dodging the immune system defenses.

But in Plenker’s hands—or rather in the CSHL’s unique facility—these notorious killers don’t kill anyone. Instead, scientists let them grow to devise the most potent ways to kill them. These tumor chunks are called organoids. They are three-dimensional assemblages of malignant growths used to study cancer behavior and vulnerability to chemotherapy and the so-called “targeted drugs”—the next generation therapies.

Scientists used to study tumors at a single-cell level, but because tumors grow as cell clusters in the body, it proved to be inefficient. The three-dimensional structures make a difference. For example, chemo might destroy the tumor’s outer cell layer, but the inner ones can develop resistance, so where single cells may die, a 3D mass will bounce back. Organoids can provide a window into these little-known mechanisms of drug resistance.

They can reveal how normal tissues turn malignant and where the cellular machinery goes off-track to allow that to happen. As their name suggests, organoids are scientists’ windows into organs, whether healthy or stricken with disease. You need to know your enemy to beat it, Plenker says, and cancer organoids offer that opportunity.

Taken from patients currently undergoing cancer treatments, these tumor chunks will reveal their weaknesses so scientists can find the cancers’ Achilles’ heel and devise personalized treatments. “Organoids are essentially patients in a dish,” Plenker says. Only unlike real patients, the organoids can be subjected to all sorts of harsh experiments to zero in on the precise chemo cocktails that destroy them in the best possible way.

And they will likely provide a more realistic scenario than drug tests in mice or rats, as animal models aren’t perfect proxies for humans.

These notorious killers don’t kill anyone. Instead, scientists devise the most potent ways to kill them.

The way that cancer proliferates in the body is hard to reproduce in the lab. Stem-cell research made it possible. After scientists spent a decade understanding how various cells multiply and differentiate into other cell types based on molecular cues and nourishment, they were able to make cells grow and fuse into tissues.

To stick together like bricks in a nicely laid wall, cells need a biological scaffold that scientists call an extracellular matrix or ECM, which in the body is made from collagen and other materials. Today, the same collagen scaffolds can be mimicked with a gooey substance called Matrigel—and then seeded with specific cells, which take root and begin to multiply.

Some tissue types were easy to grow—Columbia University scientists grew viable bones as early as 2010.1 Others, like kidney cells, were trickier. They would grow into immature tissues incapable of performing their job of cleaning and filtering blood. It took scientists time to realize that these cells wanted more than scaffolding and food—they needed to “feel at home,” or be in their natural habitat. Kidney cells needed the feeling of liquid being washed over them, the Harvard University group found, when they first managed to grow functioning kidney tissue in 2018.2

Cancers have their own growth requirements. In the body, they manage to co-opt the organism’s resources, but keeping them happy in a dish means catering to their dietary preferences. Different cancers need different types of molecular chow—growth factors, hormones, oxygen and pH levels, and other nutrients. Pancreatic adenocarcinoma thrives in low-oxygen conditions with poor nutrients.3 Glioblastomas feed on fatty acids.4 These nutrients are delivered to organoids via a specific solution called growth medium, which the lab personnel regularly doles out into the dishes.

Plenker is charged with keeping this murderous menagerie alive and well. He is the one who designs the cancers’ dietary menu, a specific protocol for each type. And while his official title is facility manager and research investigator who works closely with David Tuveson, director of the CSHL’s Cancer Center, he is essentially a cancer custodian, a curator of a unique collection that aims to change the paradigm of cancer treatment.

Plenker’s research area is pancreatic cancer—one of the most notorious killers known. Often diagnosed late and resistant to treatment, it is essentially a death sentence—only 8 to 10 percent of patients remain alive five years after diagnosis. The chemo drugs used to treat it haven’t changed in 40 years, Plenker says. In the past decade, physicians tried combining multiple drugs together with relative success. Identifying winning combos can save lives, or at least prolong them—and that’s what the organoids will help clinicians do better.

In a groundbreaking clinical trial called PASS-01 (for Pancreatic Adenocarcinoma Signature Stratification for Treatment), Plenker’s team collaborates with other American and Canadian colleagues to identify the most effective chemo cocktails and to understand the individual patients’ tumor behaviors, which would lead to more personalized treatments.5

Scientists know the same cancer types behave differently in different patients. Typically, all malignancies have the so-called “driver mutation”— the cancer’s main trigger caused by a mutated gene. But tumors also often have “passenger mutations” that happen in nearby genes. These additional mutated genes can generate various proteins, which may interfere with treatment.

Or not. Scientists call these mutated gene combinations tumor mutational signatures, which can vary from one patient to the next. With some cancers, doctors already know what mutations signatures they may have, but with pancreatic cancer they don’t have good tale-telling signs, or biomarkers. “There aren’t many biomarkers to help clinicians decide which chemo may be better for which patient,” explains oncologist Grainne O’Kane, who treats pancreatic cancer patients at the Princess Margaret Hospital in Toronto, Canada.

That’s the reason O’Kane participates in the PASS-01 trial—it will give doctors a better view into the exact specifics of their patients’ malignancies. As they take their patients’ biopsies, they are sending little cancer snippets to the CSHL to be grown into organoids, which will be subjected to chemo cocktails of various combinations to design more personalized regiments for them.

The hospital treats all patients with the so-called standard of care chemotherapy, which is more of a one-size-fits-all approach. Some patients will respond to it but others won’t, so the goal is to define the second line of chemo defense in a more personalized fashion. “That’s where the biopsies we send to Tuveson’s lab might be useful,” O’Kane says. “They can help us find something to benefit patients after the first line of chemo stopped working.”

Organoids are patients in a dish. Unlike real patients, organoids can be subjected to experiments.

Scientists can try all kinds of combos on the tumorous organoids, which they can’t do in living people. “You can treat 100 organoids with 100 different compounds and see which one works, or which compound does a good job and which ones don’t work at all,” Plenker says. That would also allow scientists to define the precise amount of chemo, so doctors wouldn’t have to over-treat patients with harsh drugs that create sickening side effects. Ultimately, organoids should take a lot of guesswork out of the process.

With about 150 patients’ adenocarcinomas already collected, the team hopes to come up with some answers. O’Kane says her team already has three patients for which they were able to design the more personalized second line of defense chemo, based on what their organoids revealed. They haven’t yet tried it, because the trial has only started recently, but this would be the next step.

“Being able to piece all this information together in real time as patients are moving through their therapies can really improve the outcomes,” O’Kane says. And while they may not be able to save all of those who graciously donated their biopsy snippets to science, it will help build better treatments in the future. “Even if we won’t be able to help these specific patients we’re hoping to use this info in the future clinical trials,” O’Kane says.

Organoids can also help understand how cancer develops. This is particularly true for breast cancers, says Camilla dos Santos, associate professor and a member of the CSHL Cancer Center. She studies the inner life of human mammary glands, more commonly referred to as breasts, and is also part of the cancer custodian crew. The hormonal changes that women go through during pregnancy subsequently modify breast cancer risk, sometimes lowering it and sometimes increasing—a complex interplay of the body’s chemicals.

“We know that women who get pregnant for the first time before they turn 25 years old, have a 30 percent decrease in breast cancer incidents later in life,” dos Santos says. “When they turn 60 or 70, 30 percent of them will not develop cancer.” On the contrary, those who are pregnant past 38 have a 30 to 50 percent increase in developing aggressive breast cancer types. Clearly, some molecular switches are involved, but they are very hard to study within the body. That’s where organoids can provide a window into the surreptitious process.

Using breast organoids, scientists can model the complex life of mammary glands at various stages of a woman’s life. And while most women wouldn’t want their breasts poked and pierced when they are pregnant or breastfeeding, many donate their tissues after breast reduction surgery or prophylactic mastectomy due to high-risk mutations like the BRCA gene.

That’s where organoids shine because scientists can not only grow them, but also give them the pregnancy hormonal cues, which will make cells generate milk, stop lactating, or do it again—and study the complex cellular interactions that take place in real life.

There’s a lot to study. At birth, mammary glands are similar in both genders—just little patches of the mammary epithelium tissue. But when puberty hits, the female glands fill up with the so-called mammary tree—a system of ducts for future milk production, which fully “blooms” in pregnancy.

“When a woman becomes pregnant, the duct tree expands, growing two types of cells—luminal and myoepithelial ones,” explains Zuzana Koledova, assistant professor of Masaryk University in Czech Republic who also uses organoids in her work. When the baby is born, the luminal cells, which line the inside of the ducts, produce the proteins that comprise milk.

The myoepithelial cells reside outside the ducts and work as muscles that squeeze the ducts to push milk out. Dos Santos likens this pregnancy mammary gland growth to the changes of the seasons. The images of sprouting ducts look like blossoming trees in the spring while later they shrivel like plants do in the fall.

The body governs these processes via the molecular machinery of hormones, which stimulate breast cells growth during pregnancy, and later cause them to die out. The two pregnancy-related hormones, prolactin and oxytocin, are responsible for milk production. Prolactin induces the luminal cells to make milk while oxytocin makes the myoepithelial cells contract. Once the baby is weaned, the levels of these hormones drop, causing cells to shrink back to their non-pregnant state.

With organoids scientists can observe these cellular dynamics at work. Koledova’s team had watched breast organoids secrete milk based on biological cues. They even recorded movies of cells pumping tiny milk droplets in the dish they were growing in. Using tiny snippets of donated breast tissue, the team grew the organoids inside the Matrigel matrix in the growth media and then added the two pregnancy hormones into the mix, explains Jakub Sumbal, a mammary gland researcher in Koledova’s group.

As they began to secret proteins that compose milk, the organoids, which looked like little domes inside the dish, changed from translucent to opaque. “At first, you can see through them, but then as they produce these proteins, they kind of darken,” Sumbal says. “And you can see them pushing out these little droplets.”

Cancer patients would no longer have to undergo chemotherapy by trial and error.

Dos Santos’s team, who also did similar work, outlined molecular changes that follow such dish-based hormonal cues in their recent study.6 In response to hormonal messages, cells produce proteins, which they display on their surfaces, like status symbols. During pregnancy the burgeoning cells prepping for milk production display the “proteins flags” that make them look important, attracting nourishment. When it’s time to die, they commit a cellular suicide.

They signal to the bypassing macrophages—immune system cleanup crew—to devour them. “They essentially say ‘come eat me!’ to the macrophages,” dos Santos says. “Because I’m no longer needed.”

The ability to mimic these processes in a dish, allows scientists to study the molecular switches that trigger breast cancer development—or minimize it. Scientists know that cancerous cells can hide from the immune system and even co-opt it into protecting themselves. They do it by displaying their own “do not eat me” protein flags on the surface and avoid destruction.

“Sometimes cancer cells can recruit specific types of immune cells to protect them,” dos Santos says. “They can not only say ‘do not eat me,’ but say ‘come hang out with me’ to the macrophages, and the macrophages will send suppressive signals to the B-cells or T-cells, the body defenders.” It is as if the cancer requests protection—a crew of guardians around it to defend against other cells that would otherwise wipe it out.

Scientists can’t telescope into the body to peek at these interactions, but they now can watch these stealth battles unfolding in a dish. “Right now we are looking at the proteins that are secreted by the organoids—the proteins that go on the surface of the organoids’ cells and what they would communicate to the immune system,” dos Santos says.

“Even when there’s no immune system surrounding them, they would still be doing that.” There’s a way to mimic the immune system, too. Scientists can add B-cells, T-cells, macrophages, and other players into the growth medium and watch the full-blown cellular warfare in action. “That’s the next step in our research,” dos Santos says.

Understanding what hormonal fluxes trigger breast cancer, and how it recruits other cells for safekeeping, can give scientists ideas for pharmaceutical intervention. “We can find drugs that pharmacologically turn off the switches that trigger cancer or interrupt its signaling for protection,” dos Santos says. “That opens novel ways to treat people.”

Can organoid research lead to a new standard of care for cancer patients? That’s the ultimate goal, researchers say. That’s why Plenker works at keeping his collection of cancer glops alive and well and thriving—he calls it a living biobank. And he keeps a stash in the cryogenic freezer, too.

He is also developing protocols that would allow commercial companies to grow organoids the same way chemical industries make reagents or mice suppliers grow rodents for research. A benefit of organoid experiments is they don’t involve animals at all.

Hospitals may one day start growing organoids from their patients’ biopsies to design and test personalized chemo cocktails for them. Once science crosses over to that reality, the entire treatment paradigm will change. Cancer patients won’t have to undergo chemotherapy by trial and error.

Instead their cancer organoids will be subjected to this process—knocked out by a gamut of drug combinations to find the winning one to use in the actual treatment. Plenker notes that once enough data is gathered about the tumors’ mutational signatures, scientists may create a database of tumor “mugshots” matching them to the chemo cocktails that beat them best.

And then just sequencing a biopsy sample would immediately inform oncologists what drug combo the patient needs. “We may be about 10 years away from that,” Plenker says, but for now there’s a lot more research to do. And a lot more cancers to grow.

By: Lina Zeldovich

Lina Zeldovich grew up in a family of Russian scientists, listening to bedtime stories about volcanoes, black holes, and intrepid explorers. She has written for The New York Times, Scientific American, Reader’s Digest, and Audubon Magazine, among other publications, and won four awards for covering the science of poop. Her book, The Other Dark Matter: The Science and Business of Turning Waste into Wealth, will be released in October 2021 by Chicago University Press. You can find her at LinaZeldovich.com and @LinaZeldovich.

Source: The Cancer Custodians – Issue 102: Hidden Truths – Nautilus

.

Critics:

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bleeding, prolonged cough, unexplained weight loss, and a change in bowel movements. While these symptoms may indicate cancer, they can also have other causes. Over 100 types of cancers affect humans.

Tobacco use is the cause of about 22% of cancer deaths. Another 10% are due to obesity, poor diet, lack of physical activity or excessive drinking of alcohol. Other factors include certain infections, exposure to ionizing radiation, and environmental pollutants. In the developing world, 15% of cancers are due to infections such as Helicobacter pylori, hepatitis B, hepatitis C, human papillomavirus infection, Epstein–Barr virus and human immunodeficiency virus (HIV).

These factors act, at least partly, by changing the genes of a cell. Typically, many genetic changes are required before cancer develops. Approximately 5–10% of cancers are due to inherited genetic defects. Cancer can be detected by certain signs and symptoms or screening tests. It is then typically further investigated by medical imaging and confirmed by biopsy.

Most cancers are initially recognized either because of the appearance of signs or symptoms or through screening. Neither of these leads to a definitive diagnosis, which requires the examination of a tissue sample by a pathologist. People with suspected cancer are investigated with medical tests. These commonly include blood tests, X-rays, (contrast) CT scans and endoscopy.

The tissue diagnosis from the biopsy indicates the type of cell that is proliferating, its histological grade, genetic abnormalities and other features. Together, this information is useful to evaluate the prognosis and to choose the best treatment.

Further reading

%d bloggers like this: