Drug combination enhanced delivery of antibacterial medications in rabbits
Mycobacterium tuberculosis bacteria.
At a glance:
A combination of approved cancer drugs may improve tuberculosis treatment.
In a rabbit model of tuberculosis, the repurposed drugs enhanced delivery of antibacterial medications.
The drugs also promoted antibacterial responses and improved health outcomes in the animals.
Next, the combination would need to be tested in patients with tuberculosis.
Researchers have identified a combination of existing cancer drugs that may improve treatment for tuberculosis.
In a study conducted in rabbits and led by Harvard Medical School researchers at Massachusetts General Hospital, the repurposed drugs enhanced delivery of antibacterial medications that target tuberculosis-causing bacteria. Findings published March 27 in PNAS.
Sometimes, patients die even after being treated, either because tuberculosis bacteria develop resistance to antibacterial drugs or because the ability to deliver medications to infected lung tissue is poor.
To address the latter challenge, researchers repurposed a pair of cancer drugs already approved by the U.S. Food and Drug Administration. The drugs were originally designed to enhance drug delivery to cancer cells by improving the structure and function of blood vessels around tumors, which can be compromised in cancer.
Blood vessel integrity is also an issue in tuberculosis: Often, the disease results in poorly functioning vessels and an overabundant extracellular matrix — the network of proteins and other molecules that surround and give structure to tissues. As a result, blood flow and drug delivery can be reduced in the abnormal lung masses where tuberculosis bacteria reside, allowing the bacteria to evade the body’s immune system.
“Our team is interested in understanding and overcoming physiological barriers to drug delivery” in tuberculosis lung masses, said senior author Rakesh Jain, the Andrew Werk Cook Professor of Radiation Oncology at HMS. “Even the most potent antibacterial drug will fail if it cannot reach the bacteria fueling the disease.”
A multidisciplinary team of engineers, cancer biologists, immunologists, microbiologists, and data analysts used a rabbit model of tuberculosis to test two drugs known as host-directed therapies, or HDTs. One, bevacizumab, acts on blood vessels, and the other, losartan, targets the extracellular matrix.
Previously, Jain and colleagues showed that bevacizumab could improve antibacterial drug delivery to tuberculosis lung masses. Now, they’ve shown that combining bevacizumab with losartan enhances this drug delivery, promotes antibacterial responses, and improves health outcomes. Surprisingly, the HTDs reduced bacteria numbers in lung masses even without antibacterial agents.
To identify the mechanisms involved, the investigators analyzed tuberculosis lung masses and other lung tissue. They found that the HDTs promoted inflammatory responses to tuberculosis bacteria in immune and nonimmune cells.
Also important, bevacizumab and losartan are approved, safe, and affordable, Jain said, so the study lays the groundwork for directly translating the results into the clinic.
A next step, he added, would be “to test these HDTs in patients with tuberculosis for the drugs’ ability to improve outcomes of antibacterial therapy.”
A flood of innovative cancertreatments helped fuel an 11.5 percent surge in spending on oncology drugs over the past year — to $107 billion globally, according to a new report. But there’s a crucial question the study can’t quite answer: How much are patients benefiting from this expanding arsenal of high-priced drugs?
The report from IMS Institute for Healthcare Informatics highlights 70 new cancer treatments, treating more than 20 types of tumors, all approved in the past five years. In the United States, where cancer drug spending was $37.8 billion last year, those new drugs alone account for $9.4 billion of the increase since 2010.
“The highlight, to us, is to see this surge of innovation in cancer treatments. … That’s a remarkable leap forward in terms of cancer care, in relatively short order,” said Murray Aitken, executive director of the IMS institute. When Aitken and colleagues look forward, they see more of the same: Close to 600 drugs are in late-stage development, and will create another wave of new treatments.
But the 72 percent increase in spending over five years in the United States raises a trickier question, too: Are cancer patients getting their money’s worth?
As $10,000-a-month cancer drugs have become a norm, doctors have begun to push back, insisting that many drugs aren’t worth the price.
“I think with the current incentive structure where the sky’s the limit [on price], it doesn’t matter if you make a great drug or a marginal drug,” said Vinay Prasad, an oncologist at Oregon Health and Science University who studies cancer drug approvals. “The problem is, I’m certain with the amount we’re spending extra, we’re not getting the commensurate value with our patients being better off.”
Not all approved cancer drugs are alike. Some may provide profound benefits, lengthening life by years; others may significantly shrink a tumor, but increase patients’ chances of survival only by small amounts. The IMS study notes that many of the recent drug approvals have had significant clinical benefits, but it does not quantify their overall impact.
Prasad’s work has found that the high prices of new cancer drugs don’t reliably reflect their novelty or how well they worked in trials. One of his studies, published last year in JAMA Internal Medicine, examined 36 drugs that were approved between 2008 and 2012 based on early indicators that they were working, such as evidence that they shrank tumors. Such measures are meant to speed up drug approvals, but there’s no guarantee that a drug that temporarily stops a tumor from growing will extend lives. Only five of the 36 drugs in his study lengthened patients’ lives, despite a median of more than four years of follow-up study.
Even if a drug is shown to be effective, the question of cost is unresolved.
One drug that is profiled in the report is a lung cancer medication called necitumumab, which costs $11,000 to $12,000 a month. It has been shown to lengthen life by 1.6 months. If its price were linked to its effectiveness, a three-week cycle would cost less than $1,500, according to a JAMA Oncology study published last year.
How price increases are washing out savings on old drugs
A key way that overall drug spending has been contained over time is through the expiration of patents and exclusivity rights that protect drugs against competition. The IMS report shows that, although the savings when drugs lose their exclusivity has been considerable, it has been counteracted by the price increases on existing drugs.
In the chart below, which breaks down the increase in oncology drug spending in the United States over the past five years, you can see how these two drivers of spending wash each other out. The effects of price increases for branded drugs approved before 2010 are shown in green: a $5.9 billion increase. This is the amount of spending that can be traced to price inflation of existing drugs, although it doesn’t account for rebates and discounts. The red bar shows the effects of loss of exclusivity on older drugs — a $4.8 billion decrease in spending that occurred when competition began.
In other countries, branded drugs approved before 2010 actually decreased in price over the same time period.
But there’s an upside to the high spending for cancer drugs in the United States: Patients here get access to more treatments than patients in other countries, Aitken points out.
The study found that, of 49 new drugs analyzed that were introduced between 2010 and 2014, only six countries — including the United States — had access to morethan half of the novel treatments.
Rebates and discounts
The report also tries to account for the effects of rebates and discounts, which drugmakers and pharmacy benefit managers secretly negotiate off of the prices listed on invoices.
Brand name list prices grew 6.4 percent between 2014 and 2015, the report found. But after discounts, the “real” growth in cancer drug prices is only 4.8 percent.
Although this does suggest that rebates and discounts are providing some relief from high list prices, it also shows that, for cancer drugs, these rebates have been markedly less than discounts for drugs, generally. A report earlier this year from IMS found that the real growth in overall drug prices, after rebates, was 2.8 percent, suggesting that the discounts were deeper for drugs treating other illnesses.
The report clearly shows that Americans get good access to cancer drugs compared to people in many other countries. What it also shows is that access comes with a price. Whether that price is a good value depends on how effective the drugs are — which, as Prasad’s research points out, is still unknown for a surprising number of drugs.
Linda H. Malkas, PhD, remembers the day a photograph for a newspaper changed her life.
“I was the Vera Bradley chair for oncology at Indianapolis University School of Medicine, and I was doing breast cancer work,” Malkas, who now serves as dean of translational science and M.T. and B.A. Ahmadinia professor in molecular oncology at City of Hope, told Healio. “I had started out as a biochemist and molecular biologist and was interested in DNA replication and repair. I probably would have kept doing that for the rest of my life. Then I met Steve Healey, who showed up to take my photo for a newspaper article.”
Running a bit late for the photo assignment, Healey explained to Malkas that his daughter, Anna, was at Riley Hospital for Children. At age 8 years, Anna had been living with neuroblastoma for almost half of her life.
“Steve took a beautiful photo of me, and as he packed up his camera and equipment, he said, ‘Dr. Malkas, what is it you do?’ I looked at him and said, ‘Come here,’” Malkas said. “We sat in front of my computer, and for 2 hours, I gave him the only thing I could: my data.”
The two wished each other luck, and that might have been the end of the story. However, Malkas kept tabs on Healey and his family. She learned that Anna died of her disease not long after she and Steve met.
When Healey contacted her sometime later asking to visit Malkas at her laboratory, he wasn’t sure she would remember him.
“I said, ‘Oh, I remember you,’” Malkas said.
From inspiration to execution
Malkas hosted Healey at her laboratory for an afternoon, introducing him to each of her young employees and discussing the group’s work.
“It was a wonderful afternoon,” Malkas recalled. “Each of my employees got up and talked for 5 to 10 minutes about what they do. Then we went down to my lab, and he did something that changed the course of my life.”
Healey handed Malkas a check for $25,000 from himself and his wife, Barbara.
“He said, ‘Dr. Malkas, we know you do all this great work on breast cancer, but if you could do something for neuroblastoma, it would mean the world to Barbara and me,’” she said. “This set the whole thing in motion.”
Malkas spoke with her husband and collaborator, Robert Hickey, PhD, associate professor in City of Hope’s department of cancer and molecular medicine, about what they had learned about DNA replication in cancer cells. The two had identified a protein that is altered in cancer cells and correlates with a change in replication fidelity.
“I asked him, ‘Do you think we could make a drug against this protein, and possibly provide a less toxic treatment to these patients?’ I was completely starry-eyed; I had no training in this. And he said, ‘Sure.’”
Malkas’ next challenge: Find a medicinal chemist to help her make this idea a reality.
She spoke with several laboratories, but none could commit the necessary time and resources. Then she received a phone call from City of Hope, asking to meet with her and discuss the possibility of bringing her to their institution.
“We talked about everything they had done during the prior 8 years,” she said. — “They had set up everything I was looking for — current good manufacturing practices facilities and the people for the regulatory process and drug discovery. They had developed the talent. Everything was there.”
When City of Hope offered Malkas a position as director of translational research, she didn’t hesitate.
“I said yes, and the first people I told were Steve and Barbara Healey,” she said. “When I told Barbara, she started to cry. She said, ‘I know if you go, something wonderful is going to happen.’”
‘I came with a target’
When Malkas began her work at City of Hope in 2011, she did so with a mandate: to develop a molecule that would shut down the protein she and Hickey had identified, proliferating cell nuclear antigen (PCNA).
“I came with a target, one that had never been drugged before,” she said. “This protein interacts with at least 200 partners in the human cell, and those are not just DNA replication repair but apoptosis, transcription and cell cycle regulation. I thought if I could shut down the form of this protein that is expressed in cancer cells, I could block not just one pathway, but a variety of pathways.”
Malkas likened this to an airport hub with multiple planes coming into terminals.
“In Indianapolis, the one way you could shut down U.S. air traffic would be with a good snowstorm,” she said. “I thought if I could make a molecule that was like a snowstorm, I’d be able to block those planes from getting into those terminals.”
Malkas and Hickey developed one molecule that came close but was not successful when put into human serum. All the while, the Healey family was never far from Malkas’ mind.
“All I could think of was that I had made a promise to this family,” she said. “I kept thinking of Anna. I needed to do something.”
When Malkas and Hickey created the molecule, she named it AOH1996, which stands for Anna Olivia Healey, the child’s full name, and 1996, her birth year.
“We sent the molecule to the NIH and when they tested it in their NCI-60 cell line panel, it had activity across the board,” she said. “If I hadn’t come to City of Hope, I don’t think I would have been able to create this drug.”
Anna’s legacy
City of Hope has initiated the phase 1 clinical trial of AOH1996, and the institution has announced that the first patient to receive the drug is doing well.
The trial, which will test the safety of AOH1996 in people with recurring solid tumors, is expected to continue for the next 2 years. Although originally studied for neuroblastoma, the pill has shown efficacy in preclinical studies treating cells from breast, prostate, brain, ovarian, cervical, skin and lung cancers.
Malkas said she and her colleagues are investigating other potential indications for AOH1996, including as a combination treatment for patients who may have difficulty tolerating cisplatin or other chemotherapy drugs.
“A lot of the time, you have to cut back on some of these drugs, because the patients’ systems just can’t take it,” she said. “So, I am thinking that this is probably where the home for this molecule will be — in combination treatment.”
Malkas praised her colleagues at City of Hope, including the trial’s principal investigator, Vincent Chung, MD, who she said brings a “quiet strength” to his role of leading the phase 1 trial, and Daniel Von Hoff, MD, who is serving as an advisor on the trial.
“The day I got the [FDA] approval, which was maybe 2 days before Christmas, I emailed Dr. Von Hoff about it. I thought of it as my Christmas present,” she said. “He emailed me back, saying, ‘I want you to know what you’ve done,’ and he sent me a chart with 350 steps on it, from the naming of the compound to getting the first patient. I was on something like step 348. I said, ‘Dan, I’m so glad I didn’t see this before.’”
Perhaps even more meaningful — the email response Malkas received from the Healey family when she notified them of the approval.
“They sent the most beautiful comments back, “she said. “I was so moved by this family who has suffered such a loss. They said, ‘Now Anna has a legacy.’”
Summary: Repurposing drugs used in the treatment of lung cancer could offer hope for symptom relief for patients suffering from chronic pain.
Source: IMBA
Pain is an important alarm system that alerts us to tissue damage and prompts us to withdraw from harmful situations. Pain is expected to subside as injuries heal, but many patients experience persistent pain long after recovery.
Now, a new study published in Science Translational Medicine points to possible new treatments for chronic pain with a surprising link to lung cancer.
The work was spearheaded by an international team of researchers at IMBA – Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Harvard Medical School, and Boston Children’s Hospital.
Their findings of the research, conducted in laboratory mouse models, open up multiple therapeutic opportunities that could allow the world to improve chronic pain management and eclipse the opioid epidemic.
Acute pain is an important danger signal. By contrast, chronic pain is based on persistent injury and can even be experienced in the absence of a stimulus, injury, or disease. Despite the hundreds of millions of people affected, chronic pain is among the least well-managed areas of healthcare.
To improve how persistent pain is managed and considering the raging opioid crisis, it is paramount to develop novel drugs based on a fundamental understanding of the underlying mechanisms.
“We had previously shown that sensory neurons produce a specific metabolite, BH4, which then drives chronic pain, such as neuropathic pain or inflammatory pain,” says project lead and co-corresponding author Shane Cronin, a staff scientist in the Penninger lab at IMBA and a former postdoc in the Woolf lab at Harvard Medical School and F.M. Kirby Neurobiology Center, Boston Children’s Hospital.
“The concentrations of BH4 correlated very well with the pain intensity. So, we naturally thought that this was a great pathway to target.”
To identify drugs that reduce BH4 levels in pain neurons, the researchers performed a “phenotypic screen” of 1000 target-annotated, FDA-approved medications. This approach allowed the scientists to start their search using medications that are currently in use for various indications, and to identify undescribed, off-target analgesic properties.
Among the first findings of this hypothesis-driven search, the team was able to link the previously observed analgesic effects of several drugs, including clonidine and capsaicin, to the BH4 pathway.
“However, our phenotypic screen also allowed us to ‘repurpose’ a surprising drug,” says Cronin. The drug ‘fluphenazine’, an antipsychotic, has been used to treat schizophrenia. “We found that fluphenazine blocks the BH4 pathway in injured nerves. We also demonstrated its effects in chronic pain following nerve injury in vivo.”
The researchers also found that the effective analgesic dose of fluphenazine in their experiments in the mouse model is comparable to the low end of the doses safely indicated for schizophrenia in humans.
In addition, the screen uncovered a novel and unexpected molecular link between the BH4 pathway and EGFR/KRAS signaling, a pathway involved in multiple cancers. Blocking EGFR/KRAS signaling reduced pain sensitivity by decreasing the levels of BH4.
The genes of EGFR and KRAS are the two most frequently mutated genes in lung cancer, which prompted the researchers to look at BH4 in lung cancer.
Surprisingly, by deleting an important enzyme, GCH1, in the BH4 pathway, the mouse models of KRAS-driven lung cancer developed fewer tumors and survived much longer. Hence, the researchers uncovered a common signaling pathway for chronic pain and lung cancer through EGFR/KRAS and BH4, thus opening up new avenues of treatment for both conditions.
Mouse sensory neurons are shown in magenta. BH4, the molecule driving chronic pain, is shown in green. Hence, the neurons “in pain” are seen in green/white. Credit: Cronin/IMBA
“Chronic pain is currently subjected to often ineffective palliative treatments. Furthermore, effective painkillers such as opioids can lead, if used inappropriately, to severe addiction. It is therefore critical to find and develop new and repurposed drugs to treat chronic pain,” says co-corresponding author Clifford Woolf, professor of neurology and neurobiology at Harvard Medical School and director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital.
One intriguing aspect of the study is the mechanistic link between pain and lung cancer.
“The same triggers that drive tumor growth appear to be also involved in setting the path to chronic pain, often experienced by cancer patients. We also know that sensory nerves can drive cancer, which could explain the vicious circuit of cancer and pain,” adds co-corresponding author Josef Penninger, IMBA group leader and founding director, who is currently also the director of the Life Sciences Institute at the University of British Columbia (UBC), Vancouver, Canada.
Abstract
Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer
Increased tetrahydrobiopterin (BH4) generated in injured sensory neurons contributes to increased pain sensitivity and its persistence. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, together with mouse genetic modeling, have demonstrated that decreased GCH1 leads to both reduced BH4 and pain.
However, little is known about the regulation of Gch1 expression upon nerve injury and whether this could be modulated as an analgesic therapeutic intervention.
We performed a phenotypic screen using about 1000 bioactive compounds, many of which are target-annotated FDA-approved drugs, for their effect on regulating Gch1 expression in rodent injured dorsal root ganglion neurons. From this approach, we uncovered relevant pathways that regulate Gch1 expression in sensory neurons.
We report that EGFR/KRAS signaling triggers increased Gch1 expression and contributes to neuropathic pain; conversely, inhibiting EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potentially druggable pathway.
Our screen shows that pharmacologic modulation of GCH1 expression and BH4 could be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents.
When a resting immune cell that is latently infected with HIV gets reactivated, the cell starts producing HIV virions (red) that bud and release from the cell (blue).NIAID/NIH
Antiretroviral therapy, the standard treatment for HIV, can remove any trace of the virus from the blood, but a hidden reservoir of HIV persists in patients who are in treatment. That means patients are never truly cured and need to be on HIV drugs for the rest of their lives.
Researchers have yet to discover a way to eliminate the virus in its latent stage, but new, early-stage research suggests a landmark cancer drug — pembrolizumab, also known as Keytruda — may be able to help. In a study published Wednesday in Science Translational Medicine, researchers looked at 32 patients that had both cancer and HIV and found that pembrolizumab, which revives the immune system and encourages it to attack tumors, also has the ability to flush HIV out of its hiding spot in immune cells.
“This is an exciting advance,” Adeeba Kamarulzaman, the president of the International AIDS Society, said in a statement. She was not involved in the study. “Being able to stop HIV from hiding is an important part of finding an HIV cure.”
HIV attacks the immune system by infecting white blood cells known as T cells. Without antiretroviral drugs, the virus will proliferate wildly through the body, obliterating the immune system and eventually leading to the patient’s death. There are effective treatments for HIV that can stop the virus from replicating and give the immune system a chance to recover.
“But treatment can’t clear latent virus,” explained Sharon Lewin, an HIV researcher at the University of Melbourne and the senior author on the study. “And you always end up with exhausted T cells.”
These cells weaken the immune system and make it harder for it to fight diseases. Exhausted T cells often make a molecule called PD1, which stands for programmed death 1, a compound that suppresses the immune system and puts immune cells in a state of stupor. At the same time, PD1 can cause HIV to go quiet as well.
“PD1 causes a bit of trouble in HIV,” Lewin said. “It means you have an exhausted immune system that can’t clear [infected] cells, but you basically also silence the virus and put it in a latent form. So, you find a lot of these latent viruses inside cells that express PD1.”
That’s where the pembrolizumab comes in. The drug, first approved by the FDA in 2014 for use against advanced melanoma, binds to PD1 and takes it out of play. In cancer, this revs the immune system up to destroy tumor cells. It’s also made the drug a blockbuster and one of the most effective treatments for a range of cancers. In HIV, it may also help the immune system hunt down the last vestiges of HIV while also disrupting the virus’ ability to hide. “It has the potential to be a double whammy,” Lewin said.
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But testing the drug’s potential in HIV treatment poses challenges, because pembrolizumab and similar cancer immunotherapy drugs can have severe toxic side effects. Boosting the immune system with them is a double-edged sword. They can lead immune cells to kill tumors, but they can also cause the immune system to become overactive and lash out against the body’s healthy tissues, too.
“It’s challenging to give anti-PD1 drugs to people who don’t have cancer. There have been small studies, but they were stopped because of the side effects,” Lewin said.
So Lewin and her collaborators at the Fred Hutchinson Cancer Research Center had to find people who were both on antiretroviral therapy for HIV and were already being treated with pembrolizumab for cancer. They found 32 individuals who fit the bill and tracked levels of HIV in their blood throughout the course of their treatment.
Patients received an infusion of pembrolizumab every three weeks for up to 105 weeks, depending on how they responded to the drug. During that time, researchers regularly collected blood and analyzed it for HIV genetic material.
After the first infusion of pembrolizumab, the team began finding HIV genetic material in the patients’ blood, suggesting the drug was forcing the virus out its sanctuary and making it again vulnerable to the antiretroviral treatment and the body’s natural defenses. But, Lewin added, it wasn’t enough to free the patient of HIV entirely.
“It released the brakes on the virus, and now they’re visible to the immune system,” Lewin said. “But this is just a proof of concept. Anti-PD1 on its own repeatedly didn’t get rid of the reservoir.”
Still, it’s an important step toward finding a cure to HIV, said Steven Deeks, a professor of medicine at the University of California, San Francisco, and an HIV expert who worked on the study with Lewin. For decades, scientists looked for a powerful weapon against the latent reservoir of HIV that can finish the infection off once and for all.
“But we now have this road map saying, ‘OK, let’s try low doses. Let’s try other ways to manipulate the system in the same pathway,’” Deeks said. “And that’s why this is an important advance.”
Experts said far more research is needed to figure out where the road map leads.
“It makes us more enthusiastic about cure efforts, but I would not say we are close,” said Shyam Kottilil, an infectious disease physician and professor at the Institute of Human Virology at the University of Maryland School of Medicine. Kottilil, who was not involved in the research, added that ” major concern is safety of these agents in people with HIV without cancer.”
Because drugs like pembrolizumab can have such severe toxicity, scientists must see if there’s a dose that can effectively do the job without causing severe side effects or death. And more broadly, scientists must still understand whether and how drugs like pembrolizumab might play a role in treating HIV, and find the best way to use these drugs to fully clear the virus from the body.
That work has already started, Lewin said, including a planned study to give a low level of pembrolizumab to patients living with HIV who don’t also have cancer. It’s possible that study might yield better results, too, she said, since the cancer may have interfered with the body’s ability to take full advantage of the drug’s effect on HIV.
“There’s a lot of avenues being tested now,” she said.
Many prescription drugs are interchangeable to some extent when it comes to treating illnesses and conditions, and now scientists have discovered that certain cancer drugs could be effective in treating those diagnosed with autism. Most experts will agree that both genetics and environmental factors lead to autism. Gene mutations are categorized into two types: germline – meaning the person is born with the mutation in almost every single cell inside them, or somatic – meaning it occurred after birth and affected only a portion of the body’s cells. But, while cancer is a disease caused by somatic mutations, autism is linked to germline mutations, so to find that these two could essentially be treated with the same drug was quite surprising.
The same happened with tuberous sclerosis complex (TSC). With this condition, benign tumors start to grow in the brain and other organs which can cause seizures, and other health complications including lung and kidney disease. When autism became more recognized as an illness clinicians began to realize that it was very common among people with TSC. Even today it’s estimated that around half of people with TSC are thought to have some form of autism. A similar thing happened with RASopathies in that many people with this condition have also been diagnosed with autism or has some autism-like qualities. Figures from 2013 show that 27 percent of people with RASopathies also meet the criteria for autism.
A deeper look into patient’s genomes also led researchers to make the cancer-autism connection. Among the first patient’s that were tested one gene that was scrutinized was CHD8, which helps to arrange DNA into its chromosomes. This gene has strong ties with cancer and the researchers fond that mutations in this gene caused a kind of subtype of autism with specific physical traits prevalent such wide-set eyes and broad foreheads. Further research carried out by Janine LaSalle, an autism researcher at the University of California, confirms the prominent link between cancer genes and autism. Their studies revealed that at least 43 genes are associated with both autism and cancer.
Charis Eng is a PTEN expert at the Cleveland Clinic in Ohio and has experience in treating dozens of children with this condition. She first made the connection between cancer and autism in 2005 and teamed up with clinical psychologist Thomas Frazier too. Together they explored how PTEN mutations affect people with autism in hopes to find targeted treatments for their patients. As part of their research, the team compared 17 children who have PTEN-ASD against 16 children with autism and large heads, 38 with just autism, and 14 with no symptoms as a control group. The results showed that compared to the others, those with PTEN-ASD had lower PTEN protein levels and enlarged volumes of white matter. Also, the children themselves had slower processing skills and a poorer memory than the other children. This indicates that low PTEN levels impair cognition by enhancing white matter abnormalities.
Currently, there is no cure for either autism or cancer, but treatment for cancer is much more common. This new link provides us with a hope that there is a clear path forward in treating autism, through the help of cancer treatments. Eng and Frazier are planning to launch their next trial very soon that will involve patients taking the cancer drug everolimus (a safer alternative to rapamycin) for six months in a bid to improve their patient’s brain function. But, until the trial is over, no one knows what the results will be. Even Frazier himself said, “In a wild, wild scenario, maybe their autism symptoms get better.” So, we will have to wait and see on that one.
Although there’s not yet enough evidence to suggest that mutations in cancer genes contribute to individual autistic qualities, it can’t be ruled out until more research has been carried out. Current studies are planning to track the development of up to 100 children with PTEN-ASD, and even if they do develop some form of cancer, there are now several different drugs available that may be able to combat it, including rapamycin which is the very same drug being used in some autism treatments. Moving forward, Eng and team will carry on looking for gene variants that could be important in autism and use cancer treatments as a way of hopefully combating them. Eng says, “Some drug companies may have these therapies already. Maybe there’s a drug they’ve shelved because it didn’t work as they’d hoped, and voila, it targets the underlying mechanism we don’t even yet know exists.”
Researchers have developed a blood test that might allow doctors to know quickly whether a cancer drug is working.
The technique is in the early stages of testing, and not ready for “prime time,” scientists said. But they were also hopeful that the research will help advance the use of so-called liquid biopsies in treating cancer.
Doctors have long used invasive biopsy procedures to get tumor samples, study them, then use the information to make treatment decisions or monitor a patient’s response to treatment.
But those procedures can be uncomfortable and carry some risks, like bleeding and infection, said Dr. Erica Mayer, a breast cancer expert with the American Society of Clinical Oncology (ASCO).
Plus, she noted, some tumors are difficult to reach, and some patients are not healthy enough to have an invasive biopsy.
So there’s been “great interest,” Mayer said, in liquid biopsy technology — which allows doctors to detect and analyze tumor DNA in a blood sample.
“It’s much more favorable for patients because it doesn’t have the potential risks of traditional biopsies,” Mayer said. It’s also easier for doctors to take repeat blood samples over time.
There are already some liquid biopsy tests on the market. Last month, the U.S. Food and Drug Administration approved the first such test that can detect particular gene mutations that affect some lung cancer patients. If they carry the mutations — in a gene called EGFR — then they may benefit from the cancer drug Tarceva.
Also last month, a large study presented at ASCO’s annual meeting reported that liquid biopsies can be a reliable alternative to traditional biopsies when it comes to detecting mutations in patients’ cancer.
That study focused on finding tumor mutations that can be targeted with available drugs, said senior researcher Chwee Teck Lim.
“For our [test], we go one step further, to see how a patient’s cancer cells will actually respond to a given drug treatment,” explained Lim, a professor of biomedical engineering at National University of Singapore.
The technique involves using “microwells” to grow clusters of tumor cells from a patient’s blood sample. Lim’s team tested the approach using blood samples from 55 women in various breast cancer treatment trials.
They exposed the women’s tumor cells to a standard cancer drug called doxorubicin and found that the better the cell clusters established themselves in the microwells, the worse a patient’s prognosis.
The technique could give feedback as quickly as two weeks after treatment has begun, the researchers report online July 13 in the journal Science Advances.
That, Lim said, means that doctors could get “crucial information” on whether a patient’s cancer is responsive or resistant to a drug — and then make a switch if needed.
But, he stressed, this was only a “proof-of-concept” study. He said his team is planning to see how the test performs when other cancer drugs, and other types of tumors, are used.
Liquid biopsies are part of the wider drive toward more “individualized therapy” for cancer, said Mayer, a medical oncologist at the Dana-Farber Cancer Institute, in Boston.
More and more “targeted” drugs are being developed, with the aim of zeroing in on specific abnormal proteins on cancer cells. Liquid biopsies are seen as a simpler, less invasive way to find out whether patients have mutations that are vulnerable to those drugs.
But the biopsies can also be used in other ways, Lim said. That includes monitoring a patient’s response to treatment.
“The rapid feedback provided by this [test] potentially allows detection of an onset of drug tolerance or resistance during the course of treatment,” Lim said. “This will enable us to immediately intervene and change treatment.”
It’s “premature,” Mayer said, to speculate on whether or how this test could eventually fit into cancer care.
For one, she noted, “what researchers see in a lab dish may not reflect what’s going on in a living being.”
But in general, Mayer said, the work being done on liquid biopsy technology is “exciting and promising.”
A cancer specialist and a medical ethicist offer their view of a “patient-centered” approach to new drug development and approval, beginning with cancer drugs.
European researchers have unraveled the genetics of an incurable subtype of acute lymphoblastic leukemia, the most common malignancy among children in industrialized nations.
Drug companies Regeneron and Sanofi have joined forces in a $2 billion commitment to develop and test new immunotherapies for cancer.
The first patient treated with a drug that targets TRK fusion proteins had significant regression of advanced soft-tissue sarcoma.
A study of clinical trials involving approved drugs — many of them cancer drugs — showed that almost two thirds of the consent forms made no mention of potential adverse effects included in the drugs’ FDA-mandated “black-box” warnings.
The colonoscopy of the future could be kinder and gentler if an investigational adjustable-focus endoscope pans out.
U.S. and Russian scientists have teamed up to examine a potential biologic basis for electromagnetic energy — the kind produced by cell phones and other wireless devices — to cause cancer.
Seven years into a diagnosis of colorectal cancer, a man and his family reflect on the financial hardship and stress caused by medical bills, despite having health insurance.
“Anthrax toxin is a professional at delivering large enzymes into cells,” Bradley Pentelute, a chemist at the Massachusetts Institute of Technology (MIT) in the US and senior author of the paper, told Anne Trafton for an MIT story on the discovery. “We wondered if we could render anthrax toxin nontoxic, and use it as a platform to deliver antibody drugs into cells.”
Now the scientists have successfully shown that they can do just that, and their research is published in ChemBioChem.
In the study, Pentelute and his team showed that they could use a “disarmed” version of the anthrax toxin to deliver two cancer-killing proteins known as antibody mimics into cells. These antibody mimics are important because they disrupt specific proteins inside cancer cells and are therefore capable of destroying them, but until now scientists haven’t been able to work out how to get them into cells.
This is the first demonstration of an effective antibody mimic delivery system, and it could allow research to develop new drugs for cancer and a range of other diseases, Pentelute explains in the MIT release.
Antibodies are proteins that are produced by our immune system to bind to pathogens, and in recent decades, scientists have designed their own antibodies that can disrupt proteins such as the HER2 receptor found on the surface of some cancer cells. Researchers have already developed a drug designed to bind to the HER2 receptor, called Herceptin, and it’s being successfully used to treat breast cancer tumours.
But the big hurdle in antibody drug research is that many of the potential drug targets are inside the cell – and scientists haven’t worked out how to get the antibody drugs there, until now.
The MIT team managed to successfully target several proteins inside cancer cells, including Bcr-Abl, which causes chronic myeloid leukaemia. The cancer cells that had the antibody mimics injected into them by the anthrax toxin underwent programmed cell suicide.
The researchers also managed to use anthrax to block a protein called hRAf-1 that’s overactive in many cancers.
“This work represents a prominent advance in the drug-delivery field,” Jennifer Cochran, a bioengineer at Stanford University in the US who wasn’t involved in the study, told Trafton for MIT. “Given the efficient protein delivery Pentelute and colleagues achieved with this technology compared to a traditional cell-penetrating peptide, studies to translate these findings toin vivo disease models will be highly anticipated.”
The MIT researchers are now testing the anthrax delivery method in mice and investigating ways they can target particular cell types.
The National Cancer Institute (NCI) has launched an ambitious new nationwide clinical trial to find out if two molecularly targeted drugs that have improved outcomes in advanced lung cancer can increase survival of patients with early-stage lung cancer that has been surgically removed.
Dana-Farber Cancer Institute researchers Pasi Jänne, MD, PhD, director, Lowe Center for Thoracic Oncology at Dana-Farber, andGeoffrey Oxnard, MD, are leading the screening phase of the trial, in which some 6,000 to 8,000 patients will have their tumors tested for uncommon genetic alterations that are associated with improved response to targeted cancer drugs. Those who have the alterations will randomly receive either a targeted drug or a placebo, and all patients will be followed for five years to determine if the drug treatment prolongs survival.
One of the genetic alterations, in the EGFR gene, is found in about 10 percent of patients with adenocarcinoma of the lung, and 5 percent have an alteration in the ALK gene.
The opening of the clinical trial, called ALCHEMIST, was announced Monday by the NCI and by two NCI organizations that coordinate clinical trials. One is the Alliance for Clinical Trials in Oncology, and the other is the ECGG-ACRIN Cancer Research Group. ALCHEMIST is an acronym for the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials.
Patients will be recruited at multiple centers across the country over the next five or six years. To be eligible, patients must already have had surgery to completely remove their lung tumors, and must have completed any adjuvant (follow-up) treatment such as chemotherapy and radiation. Samples of the removed tumor will be analyzed for the presence of EGFR and ALK mutations.
Patients found to have EGFR mutations in their tumors will be referred to a trial of the drug erlotinib (commercial name Tarceva®), while those with ALK mutations will enter a separate trial of treatment with crizotinib (Xalkori®). In each trial, patients will be randomized to the drug or a placebo. Trial leaders expect about 800 patients to receive a drug or placebo in the two treatment trials. All patients will be followed for five years, including the large number of patients who will be found to lack either mutation.
Although the Food and Drug Administration has approved erlotinib and crizotinib for treatment of advanced lung cancer, it’s not known whether the drugs will be effective in patients who have undergone complete removal of lung tumors with one of the mutations.
More than half of patients experience recurrences of lung cancer, even if it was completely removed, because tiny clumps of cancer cells invisible to the surgeon metastasize through the blood vessels to cause new cancers.
“We are excited to participate in this ambitious undertaking,” said Oxnard. “Through this large-scale collaborative effort to genotype thousands of early-stage lung cancer patients, ALCHEMIST allows us to test better adjuvant treatments while simultaneously teaching us important lessons about the genetic complexity of lung cancer.”
The trial will investigate, in addition to the potential survival benefit of the targeted drugs, each patient’s lung cancer risk characteristics, and will analyze tumor specimens when patients relapse to determine how their tumors become resistant to treatment.
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