Thoughts about adaptive therapy for Prostate Cancer ?

https://www.wsj.com/articles/a-new-approach-to-cancer-treatment-draws-lessons-from-darwin-11578414469?shareToken=st50cd5a6ea5a345a9a7b0ac6be7f97b14&reflink=article_email_share

A nascent approach to cancer treatment is using lessons from Darwin’s theory of evolution.

Called adaptive therapy, the treatment stems from the recognition that cancerous cells, just like other forms of life, mutate and evolve in response to a changing environment. Traditional cancer treatment—continuously bombarding cancer cells with drugs—can encourage drug-resistant cells to multiply, eventually creating an untreatable tumor.

Adaptive therapy doesn’t try to eradicate the entire cancer. Instead, it seeks to reduce the treatable cells, stop treatment, and wait for those cells to grow back before treating them again. The presence of the treatable cells keeps the resistant cells at bay, as they compete against each other for resources. The idea, for now, is to keep the size of the tumor in check, and manage the cancer as a chronic condition.

The concept is still largely experimental, and experts caution that it needs more trials with larger groups of patients. A few doctors are starting to bring the idea into practice—primarily for late-stage, incurable cancers. But a growing number of researchers are paying attention and looking at cancer through an evolutionary, survival-of-the-fittest perspective.

“It really is a radically different way of approaching things,” said David Agus, a professor of medicine and engineering and founder of the University of Southern California’s Lawrence J. Ellison Institute for Transformative Medicine. “The idea is ready for real, randomized clinical trials in a big sense.”

Robert Gatenby, the co-founder of Florida-based Moffitt Cancer Center’s new Center of Excellence for Evolutionary Therapy, is a pioneer in the field and driving the bulk of the work in the U.S. on adaptive therapy. He is also a co-author on a small, pilot study, with initial results published in 2017 in Nature Communications, that showed that patients lasted at least 27 months on average without their tumors growing, compared with the usual 16.5 months, while receiving less of the same drug.

Dr. Gatenby, who had a background in physics before going into medicine, often points to pest control to describe therapy, and others in the field have picked up the analogy as well. In pest management, managers often don’t try to eliminate all of the insects but instead reduce their numbers, keeping the spray-sensitive bugs around to compete against the resistant bugs. Pest management developed the technique after overusing insecticides, which eliminated most of the insects. But some resistant bugs came crawling back.

“I think pest managers are about 30 years ahead of the oncologists,” said Carlo Maley, an evolutionary cancer biologist at Arizona State University and director of the new Arizona Cancer Evolution Center.

The field combining evolution and cancer, sometimes called evolutionary oncology, is decades old. But it has gained more clinical traction in recent years as mathematical modeling has better enabled researchers and mathematicians to predict how tumors will change in response to specific treatments.

“The field is small but it’s growing,” said Christine Iacobuzio-Donahue, director of the David M. Rubenstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center, who researches cancer genetics. “Right now, people hear evolution and cancer and it’s intellectually stimulating, but we want to get past intellectually stimulating and save lives.”

The idea, however, isn’t always easy to sell, especially since cancer research and treatment has focused firmly on a cure for decades. The Moffitt pilot trial, which started in 2014 and was one of the first of its kind, had strict early stopping rules if it didn’t go well and took some convincing to get off the ground, Dr. Gatenby says.

And although the mathematical modeling predicted that the optimal time to halt treatment would be after the tumor had shrunk by 25%, the researchers decided to wait until the tumor had shrunk in half to make the concept more palatable, said Alexander Anderson, the chair of the Integrated Mathematical Oncology department at Moffitt, who works closely with Dr. Gatenby

The Moffitt pilot study originally enlisted 11 patients with late-stage, metastatic prostate cancer that was resistant to earlier treatments. The patients were put on the drug abiraterone, or Zytiga, and researchers tracked the tumors by monitoring a protein called PSA in their blood, as unusually high levels of the protein are linked to prostate cancer. Once the PSA levels dropped by half, the doctors halted all treatment until they rose again.

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The treatment length was patient-specific: Some patients cycled through the treatment regimen every few months, while others took longer. At least one patient was able to go without the treatment for over a year. Patients, on average, lasted 27 months without tumor progression by the time the initial results were released. Dr. Gatenby says that the continued treatment has extended that average to 33 months, and the project expanded to 20 patients.

The patients also cumulatively reduced the use of the drug to roughly 40% of standard dosing, Dr. Gatenby says, meaning they spend less time dealing with side effects. One month of the drug can cost upward of $6,000, according to the paper, so a pause in treatment can also save a patient thousands of dollars.

“You need less drugs, less money,” said Toni Choueiri, the director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston. “It’s a small study; there isn’t a comparative arm. But if this is true, the next thing is to take this to the next level.”


Alexander Anderson, left, and Robert Gatenby talk through ideas at the Moffitt Cancer Center. PHOTO: MOFFITT CANCER CENTER
Moffitt is currently expanding their work in applying adaptive therapy to treat prostate cancer, and the group is in the process of launching similar trials for melanoma, pediatric carcinoma, and thyroid and lung cancer. Dr. Maley and Athena Aktipis, an assistant professor of psychology at Arizona State University, are also working on opening an adaptive therapy trial for breast cancer after receiving a grant from the Arizona Department of Health Services.

“We don’t need to just look at killing tumor cells as the outcome,” said Dr. Aktipis, author of an upcoming book called “The Cheating Cell: How Evolution Helps Us Understand and Treat Cancer.” “We can look at the patient’s well being and making their lives as long and as high-quality as possible.”

Researchers aren’t sure, however, whether the technique will work with other cancers, especially those that don’t have as clear a marker as PSA. And sometimes, after the patients had been put on treatment, the drug didn’t work quite as well when the treatment restarted, said Jingsong Zhang, a genitourinary oncologist at Moffitt who treated the patients and was the first author on the pilot trial. Patients with shorter treatment cycles tended to respond better than those with longer ones.

“There are many questions,” said Dr. Gatenby. “The point isn’t that this should be broadly used. It’s the first evidence that we can use evolutionary principles to optimize therapy.”

Here is the 2019 update to the original study:
Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer (mCRPC): Updated analysis of the adaptive abiraterone (abi) study (NCT02415621) [2019]

"Abstract
Background: To achieve better prostate cancer control and to delay the emergency of treatment resistance, we developed an evolutionary game theory model using Lotka-Volterra equations with three competing prostate cancer "species": T+, Tp, and T-. T+ prostate cancer cells depend on exogenous androgen; Tp cells express CYP17A1, produce and depend on androgen; and T- cells are androgen-independent and abi-resistant. We applied this model to guide the on and off treatment cycles with abi for mCRPC. At the first interim analysis with 11 patients, this approach was shown to prolong the time to cancer progression with less than 50% drug usage compared to the conventional continuous Abi (Nat Commun. 2017). Here we present the updated data of this phase 2 study. Methods: Men with asymptomatic or minimal symptomatic mCRPC were enrolled after they achieved > 50% PSA reduction with abi as a frontline therapy for mCRPC. The primary objective is feasibility and is measured by the percentage of abi responsive men who remain to be responsive to abi (defined as > 50% decline of the pre Abi PSA) after completing 2 adaptive treatment cycles. The secondary objective is to assess the clinical benefits by comparing the radiographic progression free survival (rPFS) in men undergoing adaptive Abi therapy to the historical AA 302 trial. Results: At the data cut off in Jan 2019, the study has completed enrollment for the non-African American cohort. 15 enrolled men had > 11 months of follow up. All 15 men were off Abi for at least 3 months before abi was restarted for PSA progression at cycle 1. Seven out of the 15 men had completed at least 2 adaptive therapy cycles. Four of the rest 8 men remained on study and have not reached cycle 2. Six men were off study due to radiographic progression at month 11, 20.4, 30, 30.5, 38 and 53 from their first dose of Abi. Compare to the 16.2 months median rPFS in the AA 302 trial, the median rPFS of the 15 men would be no less than 30 months (p = 0.0068, Fisher’s exact test). Their average usage of Abi was 49% of the continuous Abi. Conclusions: Adaptive Abi therapy is feasible in men who responded to Abi as a frontline therapy for mCRPC. The updated data are consistent with our initial finding that our adaptive therapy approach can prolong the time to cancer progression with less than 50% drug usage compared to the conventional continuous Abi. Clinical trial information: NCT02415621."

Post Edited (DjinTonic) : 1/14/2020 8:02:42 AM (GMT-7)

This is basically an extension of and refinement of the long used intermittent ADT, under a different name. In this study it is specific to one drug but follows the same basic intents; being to extend the time to expected refraction, to reduce the use of the drugs, to limit or reduce side effects and to manage an incurable cancer.

Thus the method is nothing new as leading medical oncologists like Snuffy Myers, Oliver Sartor, Maha Hussein, Mark Schultz, Stephen Strum, Robert Leibovitz and others have been using and writing about the method for more than twenty years. Many men on this have used the method with both first and second line ADT.

The Life Sciences enjoy a unifying theory that has held up for more than 150 years. The Physicists are still looking for theirs. My MO defines “genetic variability” as the core challenge of cancer treatment.

While I am wishing for PC cells which would evolve into healthy PC cells and maybe even grow me a healthy prostate back(strange how that never seems to happen), I might as well wish big! How about, over these millions of years that most believe we have been evolving during, we evolve a natural resistance to PC! Those that are susceptible to PC would have died off say, 10,000 years ago. While the survivors are those naturally resistant to PC! Survival of the fittest! Now, wouldn't that have been nice? Then, I would not have even required treatment for PC! I guess there is no limit to what I am allowed to wish for.

NewspaperLover said...
PCa is overwhelmingly a disease of aging. For example, I have read thousands of posts on this Board, and do not recall ever reading a new diagnosis reported by a man under the age of 40. And not many, fortunately, under age 50. By the time PCa rears up, most men have put their “begetting days” behind them — so natural selection cannot do its terrible construction and select out only males who would not get PCa. I agree with posts above that malignant cells do not “evolve” or “adjust” in the presence of treatment — say Lupron. Rather, because of genetic variability, Lupron can only harm those cells which are hormone sensitive, leaving behind those that are hormone independent and thus free to multiply.

Excellent point about the ageing vs natural selection. But I still wish a PC cell would "evolve" into a healthy cell, rather than always supposedly in the other direction. And while PC might be out of the picture for natural selection because it occurs after our breeding years, I can still wish for all those other cancers that frequently appear at much earlier ages, to "evolve" out of the picture. Including childhood cancers. With only those not prone to such, or resistant to such, benefiting from "survival of the fittest". But alas, such has never been observed.
In the meantime, fire at a hot enough temps still kills every thing, nothing has evolved past that, has it? Cutting a prostate out BEFORE any spread still gives about 100% cure, far as I know. . The really hard trick being "BEFORE". I guess by definition, if PC starts spreading after RP, then they did not get it all, some had already escaped the gland

Post Edited (BillyBob@388) : 1/21/2020 9:33:18 AM (GMT-7)

mattam said...
"While I am wishing for PC cells which would evolve into healthy PC cells and maybe even grow me a healthy prostate back(strange how that never seems to happen)"
Lol BB! I recall my college physics professor saying that theoretically there is no reason heat couldn't flow away from a cup of water at room temperature and pressure, resulting in a cup of frozen water. It just isn't ever observed in our "reality."
Maybe one of us will wake up to a restored prostate someday. 😉

Well, while I am wishing, why not? If healthy PC cells can mutate and evolve into PC, and even PC cells evolve into badder PC cells, why can't it all go in the other direction just once, with a PC cell evolving into healthier? Yes, at my just turned age of 71, that is what I am hoping for. To wake up one day evolved right back into a man with a healthy prostate, with all connections and nerves having evolved themselves into full 18 year old function. I know that sort of thing is supposed to take millions of years, but I have seen those videos lately of bacteria "evolving" drug resistance in days, heck, even hours. So why not my prostate in say, a couple of years? I have already given it 6 years, and I'm not seeing much going on, and I'm growing impatient. ;)

Speaking of evolution -- in today's news:

Scientists uncover new mode of evolution

https://www.li vescience.com/yeast-reveals-new-mode-of-evolution.html

"Evolution and natural selection take place at the level of DNA, as genes mutate and genetic traits either stick around or are lost over time. But now, scientists think evolution may take place on a whole other scale — passed down not through genes, but through molecules stuck to their surfaces"
...
Djin