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Michael Irving, August 25, 2022
Researchers have identified a new class of drugs that could prove useful in fighting leukemia with less side effects than existing chemotherapy drugs
Scientists have identified two molecules that could help treat leukemia, in a way that’s far less damaging to healthy cells than existing chemotherapy. The compounds work using a different mechanism that’s more selective for cancerous cells, and importantly, they’re already in use for other purposes.
Abnormal activity in an enzyme called DNMT3A has previously been linked to acute myeloid leukemia, by promoting the formation of abnormal blood cells. Many current chemotherapy drugs work by disabling the DNMT3A enzyme – but unfortunately, they also interfere with the activity of DNMT1, a similar enzyme with vital roles in healthy cells. This causes many of the toxic side effects experienced by patients undergoing chemotherapy.
For the new study, the researchers investigated ways to home in on DNMT3A alone. The enzyme is known to form complexes with partner proteins while it gets to work, so the team scoured a chemical library of existing drugs until they found two that interfere with this partnering-up process.
The two compounds target a non-active site on the DMT3A enzyme
The two compounds, pyrazolone and pyridazine, target a non-active site on DNMT3A, which works to prevent it from forming complexes and ultimately stops the cascading effects that can lead to leukemia. Importantly, this mechanism means it doesn’t affect DNMT1.
The team says this breakthrough could lay the foundation for a new class of drugs, which could eventually help treat leukemia and other forms of cancer with much less toxicity than existing chemotherapy drugs. However, there’s still plenty of work left to do to uncover how it works in the long-term, and how it could be made even more potent.
Thankfully there is one less roadblock in the way – because the drugs are already in use for other diseases, it should be a more straightforward process to get them approved for use against leukemia.
The research was published in the Journal of Medicinal Chemistry.
https://newatlas.com/medical/leukemia-n ... ug-cancer/
Michael Irving, September 05, 2022
Small cell lung cancer (SCLC) is one of the deadliest forms of the disease, but now scientists may have a promising new avenue for treatment. By combining a new drug with an outdated one, the team found that they could halt growth of tumors in mice.
Most commonly occurring in smokers, small cell lung cancer is an aggressive form of the disease with a low survival rate. While chemotherapy is effective initially, the cancer can quickly develop a resistance to the drugs, leading to recurrence and progression of the disease.
For the new study, researchers at Washington University in St. Louis, Grenoble Alpes University and the University of Texas investigated how SCLC cells resist the damage caused by chemotherapy, and how that could be countered.
In previous work, the scientists found that a protein called RNF113A was implicated in cancer cells’ ability to repair alkylation damage, which is the mode of attack for common chemotherapy drugs. On closer inspection, the team discovered that RNF113A is regulated by another protein, SMYD3, which is expressed in higher amounts in SCLC cells and other cancers. In particular, higher levels of SMYD3 are linked to more aggressive cancer and stronger drug resistance.
With this new target in their sights, the scientists examined whether blocking SMYD3 could improve the effects of chemotherapy drugs. The team grafted human SCLC cells into mice, and waited until they grew tumors in their lungs. Then, they treated some mice with a drug called cyclophosphamide, some with an SMYD3 inhibitor, some with both, and some with none.
In mice given the chemotherapy alone, the tumors stopped growing for about two weeks before starting up again, indicating drug resistance had built up. But in the mice given both cyclophosphamide and the SMYD3 inhibitor, the tumors stopped growing for the entire several-month duration of the experiment. Intriguingly, the treatment worked just as well on tumors grown from a human patient whose cancer had already developed resistance to chemotherapy drugs.
Cyclophosphamide has somewhat fallen out of favor in recent decades, thanks to its stronger side effects compared to platinum-based chemotherapy agents, but the new study might mean it's worth dusting off. The team hopes that the research could lead to new treatments for an aggressive form of cancer for which there are currently few options.
“We’re talking to a number of other groups about starting a phase 1 clinical trial as soon as possible,” said Nima Mosammaparast, co-senior author of the study. “People with small cell lung cancer are in desperate need of better treatments, and I’m very excited about the possibilities here.”
The research was published in the journal Cancer Discovery.
Source: Washington University in St. Louis
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Nick Lavars, September 08, 2022
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Artist's impression of a new anti-cancer drug at work, using tiny hairs to block the oxygen supply of cells
By deploying a newly-developed drug against a key energy source of cancer cells, scientists at the Max Planck Institute for Polymer Research have developed a new way of eliminating them in mere hours. The technique relies on self-assembling molecules that take on a potent form in the cellular environment, and in doing so effectively starve the cancerous cells of the oxygen they need to thrive.
The technology at the heart of this research takes aim at one of the key metabolic functions of cells in all living things called ATP, or adenosine triphosphate. This molecule is the primary energy carrier in cells, capturing chemical energy from the breakdown of food molecules and distributing it to power other cellular processes.
Among those cellular processes is the proliferation of cancerous cells, and because of this we have seen ATP implicated in previous anti-cancer breakthroughs. The authors of the new study sought to cut off the supply of ATP, which is generated as mitochondria soak up oxygen and convert it into the molecule.
The team was able to achieve this through a newly-developed drug described as a platinum(II)-containing tripeptide. When this enters the cellular environment it responds to endogenous hydrogen peroxide by banding its molecules together to form tiny hairs, thousands of times thinner than a human hair.
“These hairs are fluorescent, so you can look at them directly with a microscope as they form,” said study author Zhixuan Zhou.
https://newatlas.com/medical/self-assem ... lls-hours/
CAR-T therapy is effective — but dangerous. An on/off switch could make it safer, faster, and cheaper.
By B. David Zarley, September 27, 2022
Presenting at the CAR-TCR Summit in Boston, researchers from La Jolla’s Scripps Research described an off/on switch for CAR-T therapy, a potentially groundbreaking safety improvement for this powerful but risky therapy.
As reported by STAT, the team from Calibr, Scripps’ drug development and discovery division, announced that the majority of patients in the nine person study responded to their experimental treatment.
Most of those had a “complete response” — meaning no signs of cancer could be detected.
But perhaps even more importantly for the future of the therapy, the researchers were also able to halt the potentially lethal side effects of the body’s immune cells. Using their new switch, they were able to turn off the souped up, cancer-killing cells and stop the side effects in days, rather than weeks.
Their technique may not only make immunotherapy safer, but also allow CAR-T cells to be tweaked to whatever cancer needs hunted — meaning off-the-shelf CAR-T cells may be possible, rather than every patient needing a custom-engineered treatment.
“It’s a very smart strategy,” Yubin Zhou, a bioengineer at Texas A&M who has kept tabs on the work, told STAT. “You can reduce the cost. I think this will win the market in the long run.”
Harnessing the immune system: At its core, cancer immunotherapy means using the body’s immune system to fight cancerous tumor cells, just like it would a bacteria, virus, or parasite.
In CAR-T therapy, researchers pull out a specific type of immune system cell, called a T cell, from the patient. These recruits are then kitted out with a “chimeric antigen receptor,” or CAR, which helps the T cells spot and kill cancerous cells. Thus armed, the CAR-T cells are put back in the patient with their new marching orders: kill the cancer!
But the immune system can have a negative impact on us, as well. CAR-T and other immunotherapies run the risk of triggering a scorched-earth attack that leads to dangerous inflammation.
This can result in a “cytokine storm,” where the overactive immune system releases too much of a protein called cytokine. The results can range from flu-like symptoms to life-threatening complications. Neurotoxicity (specifically “immune effector cell-associated neurotoxicity syndrome, or ICANS) can hurt a patient’s brain.
Unfortunately, both of these complications are common. The risk is often worth it to try to stop the cancer, but it makes mitigating the side effects crucial to better treatment. Scientists are developing numerous approaches to make immunotherapy safer, including drafting different immune cells, like the awesomely-named natural killer cells.
Another option is Calibr’s off switch.
SINC 5/10/2022 09:44 CEST
Una investigación liderada por un equipo del Instituto Hospital del Mar de Barcelona ha determinado el papel de las células que contribuyen a la formación de los tejidos, los fibroblastos, en la capacidad de los tumores de generar resistencia al tratamiento biológico más habitual dirigido contra la proteína HER2.
El microambiente que rodea los tumores en el cáncer de mama HER2 + los protege y facilita la generación de resistencia al tratamiento más utilizado contra él, el fármaco trastuzumab, un anticuerpo monoclonal. Y en este proceso, un tipo concreto de células de este microambiente, los fibroblastos, tiene un papel determinante. Estas células tienen la capacidad de bloquear al sistema inmunitario y así el tumor queda protegido. Encontrar una vía para superarlo potencia la capacidad del tratamiento para eliminar las células tumorales.
En concreto, la presencia de fibroblastos activados por TGF-beta, que expresan una molécula llamada FAP, es lo que protege de la acción de las células inmunitarias al tumor. El trastuzumab tiene la capacidad de atacar las células cancerosas que muestran niveles altos de la proteína HER2, y cuando se une al cáncer, activa una fuerte respuesta inmunitaria, que contribuye de manera muy importante a su eficacia contra el tumor.
A pesar de ello, en muchos tumores, el sistema inmunitario no es capaz de travesar el microambiente que rodea al tumor y eliminarlo. De esta manera, se genera resistencia al tratamiento y se incrementa la capacidad de este tipo de cáncer de eludir al fármaco y volver a proliferar. Un mecanismo que han podido descubrir el equipo de investigadores del IMIM-Hospital del Mar y del CIBER del Cáncer (CIBERONC), en un estudio que ha publicado la revista Nature Communications.
El trabajo también ha identificado una vía para superar esta capacidad del tumor de protegerse y de abrir la puerta al sistema inmunitario para actuar sobre las células tumorales. Mediante un modelo ex vivo, es decir, un modelo que permite trabajar con células vivas de los pacientes con cáncer de mama, los autores del estudio han comprobado como marcando con inmunoterapia la molécula FAP que expresan los fibroblastos, se puede revertir su capacidad para evitar el acceso de las células inmunitarias.
Modelo aplicable a otro tipo de tumores
“Cuando a un tumor recreado ex vivo que contiene este microambiente resistente al tratamiento, en contacto con células inmunitarias, se le añade esta molécula, FAP-IL2v, se devuelve la efectividad al trastuzumab” ha explicado Alexandre Calon, autor principal de la investigación y responsable del Laboratorio de Investigación Traslacional en Microambiente Tumoral del IMIM-Hospital del Mar. Hay que destacar que el modelo que se ha generado utiliza células humanas y también es aplicable a otros tipos de tumores.
El estudio ha validado los resultados con tres cohortes de pacientes, con más de 120 muestras. En todas ellas se ha podido comprobar cómo los niveles de activación de los fibroblastos tienen una relación directa con la capacidad del sistema inmunitario de actuar sobre el tumor. A niveles más altos, más dificultad para acceder y eliminar las células tumorales a pesar de la acción del trastuzumab.
Calon ha destacado que esto permite seleccionar mejor a los pacientes que se beneficiarán del tratamiento con FAP-IL2v dirigido a desactivar la acción del microambiente tumoral. “Si filtramos a los pacientes basándonos en estas características, podemos aislar una población de pacientes resistentes al tratamiento que se pueden tratar con esta molécula y restablecer la efectividad del tratamiento contra el cáncer de mama”, ha apuntado.
En estos momentos ya existen fármacos que se pueden utilizar para conseguir este efecto, "a pesar de que todavía habrá que llevar a cabo más estudios para evaluar su aplicación en pacientes, como indica Joan Albanell, jefe del Servicio de Oncología del Hospital del Mar, director del Programa de Investigación en Cáncer del IMIM-Hospital del Mar y coautor del estudio.
Según Albanell, “el estudio identifica los tumores en los cuales la resistencia a la terapia anti-HER2 es causada principalmente por un tipo de fibroblastos y no por otras causas. Este importante descubrimiento tendría que servir para diseñar ensayos clínicos con medicamentos que superen esta resistencia solo para aquellos pacientes en que esta resistencia está operativa. Es hacia donde tenemos que ir en la oncología de precisión”.
El trabajo ha contado con la colaboración de investigadores del Instituto de Investigación Biomédica de Barcelona (IRB) y del Instituto de Bioengeniería de Cataluña (IBEC), así como del Instituto de Investigación Sanitaria INCLIVA de Valencia y con el apoyo de la Fundación Privada Cellex, del Instituto de Salud Carlos III y la Asociación Española contra el Cáncer.
Rivas, E.I., Linares, J., et al. “Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors”. Nat Commun (2022).
The dramatic result was part of a small study testing modified viruses against difficult cancers.
B. David Zarley, October 7, 2022
A patient in a trial testing a herpesvirus-based cancer treatment saw his cancer completely disappear, and has remained cancer free in the 15 months since his treatment began, the Institute of Cancer Research (ICR) in London announced.
The outcome for West London builder Krzysztof Wojkowski was the most dramatic result seen in the small phase 1 trial of the experimental cancer therapy, called RP2. Thirty-nine patients who had exhausted all other treatment options received the treatment. Nine received the virus therapy on its own, while 30 got it in combination with immunotherapy.
“I was told there was no options left for me and I was receiving end-of-life care,” Wojkowski said in the statement. “It was devastating, so it was incredible to be given the chance to join the trial.”
Although it’s early doors, the results, which were presented at the 2022 European Society for Medical Oncology Congress in Paris, offers more evidence that cancer-killing viruses may be up to the job of snuffing out cancer where other methods have failed, and “can provide potent systemic anti-tumor effects,” the authors wrote in their poster.
The virus: RP2 isn’t just any old herpesvirus: it’s a genetically modified version of herpes simplex virus (HSV-1), the culprit behind cold sores (and an incredibly common pathogen, present in over 50% of adults in the US).
Herpesviruses, which also include the viruses behind chickenpox and genital herpes, have evolved a number of remarkable abilities, including the trick of infecting and hiding in nerve cells, from which they periodically sally forth to cause flare ups of sores or rashes, like shingles.
They also prefer to infect cancer cells. The HSV-1 in the UK trial was further modified to specifically target tumor cells, and made “oncolytic” — meaning they infect, and kill, cancer cells.
Injected directly into tumors, the virus hijacks the tumor cells, replicates, and explodes them from within — while also blocking the production of a protein called CTLA-4, which the tumor uses to hold back your immune system.
With the virus running interference, the immune system can then do what it does best: killing rogue cells.
This isn’t the first time we’ve drafted a modified herpesvirus to fight cancer — modified versions of HSV-1 have previously shown success against melanoma and brain cancer.
In fact, IRC researchers previously developed T-Vec, a virus approved by the NHS for treating skin cancer. Lead researcher Kevin Harrington told the BBC that RP2 is like T-Vec with even more teeth.
“It’s had other modifications to the virus so that when it gets into cancer cells it effectively signs their death warrant,” Harrintgon said.
The trial: The ongoing phase 1 trial, run with the The Royal Marsden NHS Foundation Trust and sponsored by RP2’s manufacturer Replimune, was designed to test the safety and best dosage for the drug, as well as its ability to shrink several different kinds of tumors.
It has enrolled thirty-nine patients whose cancers have not responded to other treatments.
Of the nine patients who only received RP2, three saw results. Two of them, one with oesophageal cancer and the other with a rare eye cancer called uveal melanoma that had spread to the liver, had their tumors shrink, with the cancer’s progression still halted 15 and 18 months, respectively, after treatment.
The other patient, West London builder Wojkowski, had his salivary gland cancer completely wiped out.
Of the 30 patients who received RP2 along with an immunotherapy called nivolumab, seven of them responded to the combined drugs. Melanoma, uveal melanoma, and head and neck cancer patients all had their cancer’s growth stop or shrink. After 14 months, there had still been no progression in six of the seven cancers.
When patient’s tumors were biopsied before and after injection, they found evidence that herpes was working to activate the immune system, with more immune cells present around the tumor. The drug caused mild side effects, including fever, chills, and fatigue.
Although a small and still ongoing trial, these early results are promising, Jonathan Zager of Tampa’s Moffitt Cancer Center told Insider.
“We’ll see some more studies done in the very near future, and I’m excited — certainly not disheartened or skeptical,” Zager said.
Next steps: “Our study shows that a genetically engineered, cancer-killing virus can deliver a one-two punch against tumours – directly destroying cancer cells from within while also calling in the immune system against them,” Harrington said in a statement.
The next step is to continue testing RP2 in more patients, to see if its efficacy holds up, especially against cancers that resist current treatments.
“Viruses are one of humanity’s oldest enemies, as we have all seen over the pandemic,” Kristian Helin, the chief executive of IRC, said.
“But our new research suggests we can exploit some of the features that make them challenging adversaries to infect and kill cancer cells.”
Michael Irving, October 19, 2022
A new cancer treatment pairs an acidity-seeking molecule with an immunotherapy drug Depositphotos
Researchers at Yale and the University of Rhode Island (URI) have demonstrated a new technique to fight cancer by attaching immunotherapy drugs to a molecule that seeks out the acidic environment of cancer cells. In tests in mice, a single dose was enough to eradicate even advanced tumors.
Our greatest weapon against cancer – and indeed all disease – is our immune system, but even it needs a helping hand sometimes. Immunotherapy provides that helping hand, with one method being what are called immune checkpoint inhibitors. These drugs effectively take the natural brakes off the immune response, allowing it to battle against cancer for longer.
As promising as these drugs seem so far, they don’t work on “cold” tumors that have little immune activity to start with. So another type of drug known as STING agonists are designed to fire up these cold tumors into hot ones that are more receptive to immunotherapy. But these also have their drawbacks – namely, it’s hard to target them to cancer cells.
And that’s where the new study comes in. The researchers from Yale and URI used a molecule called pH-low insertion peptide (pHLIP) to guide the drug to where it needs to go. pHLIP is drawn to acidic environments, conveniently like the kind that cancer makes around itself.
“When pHLIP encounters a cell membrane with a neutral pH, it will sit on the surface briefly and then pull away,” said Donald Engelman, co-author of the study. “But if it’s in an acidic environment, then the peptide folds into a helix, crosses the cell membrane and stays there.”
An untreated tumor (top left) is highly acidic, as seen with its fluorescence profile (top right). Within days of the new treatment however, the tumor (bottom right) starts to shrink and its acidity goes down (bottom right)University of Rhode Island
The team coupled pHLIP to STING agonists, so that the former carries the latter to cancer cells and helps them inside to get to work. And tests in mice proved promising – the researchers administered pHLIP-STING to 20 mice with small colorectal tumors and found that after a single injection, the tumors disappeared entirely in 18 mice within a few days. In another group with larger tumors, seven out of 10 mice saw their tumors disappear completely.
By comparison, another group of 10 mice received just STING without the guidance of pHLIP. Tumor growth slowed slightly in all 10, but tumors remained.
The treatment even seemed to have a long-lasting effect. The team injected new cancer cells into treated mice that had been tumor-free for 60 days – and no new tumors developed, indicating an immune memory had formed.
While the technique sounds promising, the usual caveats apply – the results of animal tests don’t always carry across to humans. Far more work needs to be done before any potential treatment based on pHLIP-STING could find use.
The research was published in the journal Frontiers of Oncology.
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Rich Haridy, November 06, 2022
A therapeutic vaccine being trialed is designed to help the immune system better target breast cancer by homing in on a certain protein over-expressed by tumors
A new paper in the journal JAMA Oncology has reported the results of a decade-long Phase 1 human trial testing an experimental breast cancer vaccine. The novel treatment was found to be "very safe" and a larger Phase 2 trial is now underway testing efficacy.
Up to 30% of breast cancers involve the overproduction of a protein called human epidermal growth factor receptor 2 (HER2). These HER2-positive cancers are often more aggressive than other types of breast cancer, growing faster and being more likely to reoccur.
For the last couple of decades one of the more effective clinical treatments for this type of breast cancer has been a monoclonal antibody therapy designed to block the activity of HER2 on tumor cells. However, researchers have long been working on vaccines that can train the immune system to target these HER2-positive tumor cells.
These kinds of cancer vaccines are not designed to be preventative vaccines that stop cancers from appearing in the first place. Instead, these are known as therapeutic vaccines, given to patients after they are diagnosed with a cancer in the hopes they help the immune system better seek and destroy certain tumors.
In this instance researchers are working with what is called a DNA vaccine. These vaccines deliver DNA blueprints for the production of certain proteins into the nucleus of a cell. That protein is then produced by the cell, triggering an immune response. The vaccine being tested prompts cells to produce a specific fragment of the HER2 protein.
This Phase 1 trial began 20 years ago, slowly enrolling 66 patients with advanced HER2-positive breast cancer. Three different dose levels were tested, with the primary goal of the trial to evaluate the long-term safety of the vaccine. Because HER2 proteins can be found on other cell types in the body, the researchers planned a 10-year follow-up for each participant to make sure there were no lingering problems of immune activity against healthy tissue.
“The results showed that the vaccine was very safe,” said lead author on the new study Mary Disis. “In fact, the most common side effects that we saw in about half the patients were very similar to what you see with COVID vaccines: redness and swelling at the injection site and maybe some fever, chills and flu-like symptoms.”
The trial was not geared to evaluate how effective the experimental vaccine is at treating breast cancer. But Disis did point out promising early signs of efficacy, with 80% of the treated trial participants surviving the full 10-year follow-up. Disis said only around 50% of patients with advanced HER2 breast cancer would generally be expected to survive more than five years, so it's likely the vaccine is working.
A Phase 2 trial is currently underway, testing the vaccine's efficacy in a larger cohort of HER2-positive patients. That trial kicked off a few years ago and only has a two-year follow-up period. So preliminary results could start coming within the next couple of years.
“If the results of the new randomized-controlled Phase 2 trial of the vaccine are positive, it will be a strong signal for us to rapidly move forward to a definitive phase III trial,” Disis added. “I have high hopes that we’re close to having a vaccine that can effectively treat patients with breast cancer.”
The new study was published in JAMA Oncology.
Source: UW Medicine
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Martin Luther King