(Press-News.org) LOS ANGELES - Patients with advanced colorectal cancer may be spared from a toxic side effect caused by a type of targeted therapy used to treat the cancer with the help of another drug normally used to treat melanoma, according to a study led by researchers at the UCLA Jonsson Comprehensive Cancer Center and Memorial Sloan Kettering Cancer Center.
For the past decade, epidermal growth factor receptor (EGFR) inhibitors have helped prolong the lives of patients with many advanced cancers, including cancers in the lung, head and neck, colorectal, breast, bladder and pancreas. While these targeted therapy drugs are highly effective at keeping the cancer at bay, they can cause patients to develop acneiform lesions, a type of skin rash that looks like acne bumps and frequently leads to impaired quality of life and drug discontinuation.
Between 75% to 90% of patients on this treatment suffer from acneiform rash, and there is currently no FDA approved treatment for this side effect.
"A majority of patients with advanced colorectal cancer are treated with these types of drugs at some point in their treatment," said study co-author Dr. Zev Wainberg, associate professor of medicine at the David Geffen School of Medicine at UCLA and director of the early phase clinical research program at the Jonsson Cancer Center. "And when patients experience this type of difficult rash -- which is very common -- we have very limited options other than antibiotics, decreasing the dosage or discontinuing the treatment altogether."
In order to eliminate the rash, researchers looked to BRAF inhibitors, a relatively new cancer therapy used to treat melanoma. In the laboratory, UCLA researchers discovered that BRAF inhibitors could also be used to help speed up how the skin repairs itself from injury and lessen skin-related side effects.
BRAF inhibitors given in pill form work by blocking a mutated gene found most commonly in melanoma, which rapidly shrinks the tumors. This can also set off a cellular cascade in other skin cells in a process called paradoxical MAPK activation, which lead to increased signaling and proliferation.
A team at Lutris-Pharma working with Dr. Antoni Ribas, professor of medicine and director of the tumor immunology program at the Jonsson Cancer Center, developed a topical BRAF inhibitor that can be applied directly on the skin, called LUT014. They found in laboratory models that the therapy induces paradoxical MAPK activation of skin cells and offsets the negative effects of EGFR inhibitors. The cancer is being inhibited by the EGFR inhibitor, but the cream is letting the skin go back to normal by activating this pathway, said Ribas.
"It's a new, original idea to address the more common toxicity from the class of drugs that have improved the treatment of patients with colorectal cancer," said Ribas, who is also the senior author on the study. "We saw a dramatic improvement using BRAF inhibitors in the laboratory and hoped it might improve the EGFR inhibitor-induced rashes in patients."
To test the topical administration of LUT014, researchers enrolled 10 patients with metastatic colorectal carcinoma who developed grade 1 or 2 skin rash (with grade 2 being worse) while on therapy with EGFR inhibitors cetuximab or panitumumab. They were separated into three different cohorts with dosages of 0.3, 1 or 2.5 mg/g of LUT014 and were treated for 28 days.
All three patients in the first cohort received the 0.3 mg/g dosage and all improved from a grade 2 rash to a grade 1 rash. In the second cohort, four patients received the 1.0 mg/g dosage and started with a grade 2 or grade 1 rash. The two patients who had a grade 2 rash improved to a grade 1 rash and the two patients who started with a grade 1 rash did not see a change of grading with the treatment. On the third cohort, three patients received 2.5 mg/g, two starting with a grade 2 rash and one starting was a grade 1 rash. One of them improved, another stayed stable and another experienced worsening of the skin rash.
Overall, 6 out of the 10 patients showed a reduction in severity of the rash and the improvements were maintained a month after treatment. The lower dosages of the treatment fared better than the higher dose. No dose limiting adverse effects were noted.
"Until now, we haven't had any original solutions to really address these common, painful rashes," said Wainberg, who is also the co-director of the UCLA gastrointestinal oncology program. "This study demonstrated that you can eliminate the rash in a more logical and mechanistic way."
INFORMATION:
The study was published in Cancer Discovery, a journal of the American Association for Cancer Research.
The next phase of the trial, conducted by Lutris-Pharma is designed to include nearly 120 patients in center across the U.S. and Israel. Interim results are expected by the end of 2021.
LUT014 is developed by Lutris-Pharma, a clinical stage biopharmaceutical company focusing on topical therapies for reducing dose limiting side effects of cancer agents.
Disclosures
Ribas is founder and director at Lutris-Pharma.
OAK BROOK, Ill. - An automated system that uses artificial intelligence (AI) is effective at detecting a common type of wrist fracture on X-rays, according to a study published in the journal Radiology: Artificial Intelligence. Researchers said the AI-derived algorithm could help speed diagnosis and allow earlier treatment.
Scaphoid fractures are injuries to one of the small bones of the wrist that typically occur when people try to break a fall with their hands. They comprise up to 7% of all skeletal fractures. Prompt diagnosis is important, as the fracture may fail to heal properly if untreated, leading to a host of problems like arthritis and even loss of function.
Conventional X-ray is the imaging technique of choice for diagnosing scaphoid ...
Studying the violent collisions of black holes and neutron stars may soon provide a new measurement of the Universe's expansion rate, helping to resolve a long-standing dispute, suggests a new simulation study led by researchers at UCL (University College London).
Our two current best ways of estimating the Universe's rate of expansion - measuring the brightness and speed of pulsating and exploding stars, and looking at fluctuations in radiation from the early Universe - give very different answers, suggesting our theory of the Universe may be wrong.
A third type of measurement, looking at the explosions of light and ripples in the fabric of space caused ...
Under the background of global warming, the energy budget of the earth is out of balance with more than 90% of additional heat entering the ocean.
The tropical Pacific Ocean has an important influence on the global tropical climate and the climate of China, and the tropical Pacific Western Boundary Currents (WBCs) that flow through it plays an important role in the climate system. Large-scale ocean circulation redistributes ocean heat and mass and is hence one of the basic dynamic processes that shape the earth's Marine environment. The tropical Pacific WBCs system is a key part of the global ocean circulation system. ...
It is challenging to analyze proteins at low concentrations, especially for those in a mixture of various conformations such as intrinsically disordered proteins (IDPs). A research team led by Prof. HUANG Jinqing, Assistant Professor of Department of Chemistry at The Hong Kong University of Science and Technology (HKUST), has developed optical tweezers-coupled Raman spectroscopy that can directly probe the structural features of alpha-synuclein, an IDP closely linked to Parkinson's disease, at the physiological concentration by focusing on individual protein molecules.
IDPs play an important role in biological processes and many of them are associated with incurable neurodegenerative ...
Researchers from the Universities of Bristol and Surrey have found that well-fitting, three-layered cloth masks can be as effective at reducing the transmission of COVID-19 as surgical masks.
At the height of the COVID-19 pandemic, 139 countries mandated the use of face coverings in public space such as supermarkets and public transports. The World Health Organization also advises the use of face coverings and offers guidance on their effective features. Face coverings suppress the onward transmission of COVID-19 through exhalation and protect the wearer on inhalation.
In a paper published by the Physics of Fluids journal, the researchers detail how they looked at how liquid ...
Areas in Sweden with early access to electricity at the start of the 1900s underwent rapid change. Electrification led to more strikes, but it was not those who were threatened by the new technology who protested. Instead, it was the professional groups who had acquired a stronger negotiating position - thanks to technological development, according to new research from Lund University.
Labour market conditions are affected by new technology. Currently, the impact of automation on the labour market is often discussed, whether jobs will disappear as computers take over, or whether digitalisation drives development towards a gig economy with uncertain employment conditions. One fear is that the technological development could generate social unrest and a risk of increased ...
Like a chameleon of the night sky, the Moon often changes its appearance. It might look larger, brighter or redder, for example, due to its phases, its position in the solar system or smoke in Earth's atmosphere. (It is not made of green cheese, however.)
Another factor in its appearance is the size and shape of moon dust particles, the small rock grains that cover the moon's surface. Researchers at the National Institute of Standards and Technology (NIST) are now measuring tinier moon dust particles than ever before, a step toward more precisely explaining the Moon's apparent color ...
Researchers from the University of Copenhagen, in collaboration with their Swiss colleagues at the University Hospital of Bern, have cracked the code for controlling a group of enzymes that affect our metabolism.
The researchers' findings could help us avoid diseases ranging from high cholesterol to infertility to certain types of cancer, which are all due, among other things, to hormonal imbalances.
They have found a way to influence a special protein called cytochrome P450 reductase (POR) -- popularly characterized as the 'conductor' of the body's protein orchestra, which helps regulate our hormones and makes it possible to break down medicinal products in the liver.
"We have developed a method to ...
Fast growth of the global human population has long been regarded as a major challenge that faces mankind. Presently, this challenge is becoming even more serious than before, in particular because many natural resources are estimated to deplete before the end of this century.
The increasing population pressure on agriculture and ecosystems and the environment more generally is predicted to result in worldwide food and water shortages, pollution, lack of housing, poverty and social tension. The situation is exacerbated by global climate change as considerable areas of land are predicted to be flooded and hence taken out of human's use.
It is widely believed ...
According to the researchers, three songs from a playlist are enough to identify the person who chose the songs. Hence, companies like YouTube and Spotify can accumulate a great deal of information about their users based only on their musical preferences.
The study was led by Dr. Ori Leshman of the Jaime and Joan Constantiner School of Education at Tel Aviv University and Dr. Ron Hirschprung of the Department of Management and Industrial Engineering at Ariel University. The study was published in the journal Telematics and Informatics.
The study included ...
