An anticancer drug opens a new avenue for the treatment of Parkinson. Once they enter the body, the drugs, in addition to carrying out their therapeutic function, are biochemically transformed by the action of the metabolic machinery, a process that facilitates their expulsion. This biotransformation involves a gradual disappearance of the drug, which is converted into its metabolites.
Rucaparib, the anticancer drug that opens new therapeutic avenues for Parkinson's disease
These, in turn, can reach high concentrations in the body and also demonstrate a biological activity that can be different from that of the original drug. That is, the metabolites and the drug coexist in the body and can cause effects different from those obtained with the individual molecules.
This is the case of Rucaparib, a drug used in chemotherapy for ovarian, breast and, more recently, prostate cancer, and its metabolite, the M324 molecule. Rucaparib is part of a group of drugs designed to treat several types of cancer that show changes in DNA repair. Specifically, they are inhibitors of the PARP1 enzyme, involved in the process of repairing mutations in the genetic material.
One study
conducted by researchers Albert A. Antolin, of the Oncobell program of the Bellvitge Biomedical Research Institute (IDIBELL) and ProCure of the Catalan Institute of Oncology (ICO), and Amadeu Llebaria, of the Institute of Advanced Chemistry of Catalonia (IQAC- CSIC) , demonstrated that Rucaparib and its major metabolite M324 exhibit differential activities.
Published in the journal Cell Chemical Biology, the article analyzed Rucaparib and M324, making a computational prediction of the metabolite's activity. The article describes the synthesis of M324 and its bioassay, demonstrating that the drug and its metabolite have differentiated activities and act synergistically in some prostate cancer cell lines.
Surprisingly, M324 reduces the accumulation of the protein α-synuclein (an important component of Lewy bodies) in neurons derived from patients with Parkinson's disease, a neurodegenerative disease characterized by a movement disorder and in which neurons do not produce sufficient quantities of the neurotransmitter dopamine.
Specifically, the demonstrated synergy between Rucaparib and M324 in prostate cancer cell lines could impact clinical trials in advanced stages of this type of cancer. On the other hand, the fact that M324 is able to reduce the abnormal accumulation of α-synuclein in stem cell-derived neurons of a Parkinson's patient highlights the therapeutic potential of this metabolite and its possible pharmacological application for the treatment of this neurodegenerative disease.
These results were obtained thanks to the collaboration of the IDIBELL and ICO groups led by Miquel Àngel Pujana and Álvaro Aytés, and the group of Antonella Consiglio, IDIBELL and UB.
The researchers used computational and experimental methods to comprehensively characterize the pharmacology of the M324 molecule for the first time. The first author of the work, Huabin Hu, made a comprehensive prediction of the differential activity of the original drug and its product, which results in different spectra of the phosphorylation pattern of cellular proteins.
Carme Serra, from the MCS group at IQAC-CSIC, synthesized the M324 metabolite, which enabled experimental verification of computational prediction in biological and cellular assays. The results obtained could have implications for clinical treatment with Rucaparib and, in turn, open up new opportunities for drug discovery.
In summary, the study points towards a new conceptual perspective in pharmacology: one that considers drug metabolism not as an unwanted process that degrades and eliminates the therapeutic molecule from the organism, but rather as a process that may have potential advantages from a from a therapeutic point of view. Indeed, the work highlights the importance of characterizing the activity of drug metabolites to comprehensively understand their clinical response and apply it in precision medicine.
An international research team led by Krembil Brain Institute neurologist and senior scientist Dr. Anthony Lang has proposed a new model for classifying Parkinson's disease.
Over the past few decades, researchers have discovered several biological factors underlying Parkinson's disease. Key factors include an accumulation of the protein α-synuclein in the brain, which leads to the degeneration of neurons, and genetic factors that increase the risk of developing the disease. They have also begun to develop reliable methods for testing these factors, called biomarkers, in living patients.
Despite these advances, doctors continue to diagnose the disease based on clinical features, such as the presence of tremors and other common motor symptoms.
According to Dr. Lang, holder of the Lily Safra Chair in Movement Disorders at University Health Network (UHN), the Jack Clark Chair in Parkinson's Disease Research and a professor in the Department of Medicine at the University of Toronto , this traditional approach to diagnosing Parkinson's disease does not take into account the complex biological processes at play.
“We know that Parkinson's exists in the brain for one to two decades, or more, before clinical manifest
ations arise,” says Dr. Lang. “Therefore, we believe that current research should be guided by the biological determinants of the disease, rather than limited clinical descriptions of its signs and symptoms.”
He adds: “We need a radically different way of looking at this disease.” In a recent paper published in Lancet Neurology, Dr. Lang's team proposed a new biology-based model for classifying Parkinson's disease, called SynNeurGe (pronounced “synergy”).
The model highlights the important interactions between three biological factors that contribute to disease:
the presence of pathological α-synuclein in the brain (S);
evidence of neurodegeneration, which occurs as the disease progresses (N); AND
the presence of genetic variants that cause or strongly predispose a person to the disease (G).
According to the team, this “SNG” classification system better explains the biological heterogeneity of Parkinson's disease and the many ways the condition can present in patients.
As a result, the system could help researchers identify subgroups of patients exhibiting distinct disease processes and develop clinically meaningful disease-modifying therapies.
“We must recognize that Parkinson's disease can differ greatly from one patient to another. We are not dealing with a single disorder,” explains Dr. Lang. “Our model provides a much broader and more holistic view of the disease and its causes.”
“With this new model, Dr. Lang is leading a truly fundamental international effort to redefine the biological complexity of Parkinson's disease, which will lead to more advanced and streamlined research in this area and, ultimately, precision medicine for patients,” says Dr. Jaideep Bains, co-director of the Krembil Brain Institute at UHN.
The team is confident that this new way of looking at Parkinson's disease will help researchers study its molecular basis, distinguish it from other neurodegenerative conditions that share common biological characteristics, and identify targets for new therapies.
Despite these potential applications, Dr. Lang cautions that the model is intended for research purposes only and is not ready for immediate application in the clinic. Yet, it is already sparking hope among patients and the medical community.
“The ability to personalize treatments improves when you can identify exactly what is going on in a specific patient like me,” says Hugh Johnston, founding chair of the Movement Disorders Patient Advisory Board at UHN's Krembil Brain Institute, who currently lives with Parkinson's disease. “This new way of thinking is what we've been waiting for. It's a game changer.”
“Without looking at biology, you can't get answers. And without answers, we won't have much-needed progress in Parkinson's,” says Dr. Lang. “This new classification system and the future research project it will inspire are one of the most exciting things I have worked on in my career.”
More men than women are diagnosed with Parkinson's disease. The why is still followed by a big question mark, but sexual difference is nevertheless a topic of growing interest for researchers.
A group of researchers from Aarhus University, led by Professor Marina Romero-Ramos, may have found one of the pieces of this puzzle.
In a paper recently published in npj Parkinson's Disease, researchers shed light on a specific receptor called CD163, a protein expressed primarily in phagocytic immune cells in the blood.
The protein is involved in the immune response during the neurodegenerative process associated with α-synuclein aggregation in Parkinson's disease, and appears to play a specific and protective role in the body's defense against disease-related damage.
“Our study suggests that CD163 is involved in the mechanism that controls the entry of lymphocytes into the brain during neurodegeneration,” explains Romero-Ramos.
The most interesting thing is that the protein seems to exert a particularly relevant neuroprotective role in females.
The findings therefore add new information on the sex difference related to Parkinson's disease and suggest that some of the responses may be expressed in the body's protection system.
“We believe that the observed sex differences in the risk of developing Parkinson's disease, higher in males, as well as the disparities in disease presentation between the sexes could be due to differences in immune response,” explains Romero-Ramos.
This study provides evidence that increased CD163 expression in Parkinson's disease patients may be a compensatory mechanism aimed at protecting neurons, especially in women. Romero-Ramos hopes the study will increase research attention both on the immune system and on the involvement of sex differences in the disease.
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