Goal
Throughout my scientific career, I have noticed a growing disconnect between the scientific community and non-scientists. I believe this is due to a lack of communication between scientists and non-scientists. To address this issue, I will write plain language summaries describing recently published, high-impact scientific findings for non-scientific audiences.
Posted: 9/9/24
A potential 1-2 punch to knock out glioblastoma
Glioblastoma (GBM) is an aggressive and hard to treat brain cancer, with a median survival of 12-16 months. Recent studies in GBM cell lines suggest that antipsychotic drugs could be repurposed for use in GBM patients. Pimozide, a drug used in Schizophrenic patients, while not effective on its own in GBM mouse models, was highly effective in combination with radiation. Thus, further investigation into pimozide used in combination with other drugs is a promising GBM treatment route.
A study published in Cell Reports Medicine last week found that while pimozide did cause high levels of cell death in GBM cell lines, GBM cells eventually became resistant to pimozide. GBM cells developed resistance by increased consumption of glutamine, an amino acid, and fat production. Treating cells with pimozide and inhibitors of glutamine metabolism, ASCT2 and glutaminase, overcame this resistance and caused high levels of cell death in GBM cell lines, patient-derived GBM tumors, and mouse models of GBM. Importantly, these combination therapies increased lifespan in mouse models of GBM.
Collectively, this study provided valuable insight into pimozide’s mechanism of action in GBM cells and identified a treatment combination that may be applied to human GBM patients. Notably, pimozide has shown promise in treating other types of cancer, and has already been tested in a Phase I oncology clinical trial, which should expedite the clinical trial process. The use of pimozide in clinical trials will be interesting to follow going forward.
Posted: 9/3/24
Targeting glucose metabolism to treat Alzheimer’s Disease
With advancements in modern medicine, people are living longer, which has coincided with a substantial increase in the prevalence of Alzheimer’s Disease (AD). Currently, effective treatments are limited, thus driving the need for the identification of new targets and development of novel treatments.
A great deal of research has focused on clearing protein aggregates, hallmarks of AD and other neurodegenerative diseases, to treat AD. However, this avenue has not been as effective as predicted. Over the last 5-10 years, several studies have found that sugar metabolism is rewired in brain cells of AD patients, which may contribute to disease pathology.
A recent study found that inhibition of a metabolic protein that is upregulated in AD models, IDO1, restored metabolic activity in multiple types of brain cells, including neurons, the functional cellular unit of the brain. Excitingly, restoration of metabolic activity significantly improved memory in mouse models of AD. This study was quite robust, as the scientists inhibited IDO1 using multiple methods in cultured mouse and human cells, as well as live mouse models of AD. Collectively, the data presented suggest that targeting IDO1 is a promising route to treat AD.
Perhaps the most promising outcome of this study is that reversal of AD pathology was accomplished by inhibiting IDO1 with a drug developed by Pfizer (PF-0680003), that was recently tested in a Phase I clinical trial to treat a form of brain cancer. While the study did not progress to Phase II, the IDO1 inhibitor, seemed to be fairly safe, which should expedite the process to testing its safety and efficacy in AD patients. Based on the strong efficacy observed in the AD study, it would be surprising if clinical trials to test PF-0680003 in AD patients were not in the works.
Posted: 8/26/24
A promising new technology to measure the potential of cancer metastasis
Metastasis, the spread of cancer cells from one organ to another, complicates the design of a treatment plan and significantly reduces survival probability. A primary mechanism of metastasis depends on a cancer cell’s ability to shrink itself to fit through tight spaces separating an organ from the bloodstream thus, allowing it to spread to other organs.
A recent study published in Science Advances developed a new technology that measures metastatic potential by quantifying the ability of cancer cells to shirink themselves and pass through narrow openings. Using minimally invasive and highly invasive cancer cell lines, the authors confirmed the technology could measure invasiveness with high accuracy, and therefore metastatic potential. Importantly, the newly developed platform far exceeded the sensitivity level observed in currently used technology.
Notably, the new platform can be combined with a 96-well plate to run automated, high-throughput assays, an important improvement for the cancer drug discovery community. Lastly, this platform is compatible with imaging and biophysical technology that can identify specific features of the metastatic mechanism that are affected by a particular drug, which is important for preclinical drug development and potentially identifying drugs that can have additive effects for later stages of clinical trials.
In the near-term, this platform may impact the aggressiveness of treatment plans at the clinical level, while improving the speed and rigor of preclinical drug discovery. In the long-term, the impact on drug discovery will hopefully bring new, more effective drugs and treatments to the clinic. Going forward, it will be interesting to follow the use and advances of this technology, potentially in the biotech and pharmaceutical realm. This technology would seem to be a prime centerpiece of an academic spinout and/or collaboration with existing companies.
Posted: 8/19/24
A potentially general target to reduce severity of respiratory infections
Respiratory infections are some of the deadliest diseases in the world, causing a major healthcare burden each year. However, why one patient may be effected more severely than another is unclear. Identification of early markers for severity could enhance treatability and patient outcomes.
A study published in Cell linked increased expression of a gene that promotes fat production (OLAH) with respiratory disease severity. OLAH expression was consistently higher in patients with severe avian flu (AH7N9), seasonal flu, COVID-19, RSV, and multisystem inflammatory syndrome in children (MIS-C) than uninfected individuals or patients with mild effects.
Remarkably, genetic inactivation of OLAH in mice made them more resilient to a lethal flu infection. Mice survived longer, exhibited less tissue damage and inflammation, and there was a reduced viral load in the lungs. Going the other direction, feeding mice oleic acid, the primary product of OLAH activity, enhanced infection severity.
Collectively, this study firmly establishes OLAH expression as a key biomarker of infection severity, as well as a potential drug target. Importantly, the expression pattern was consistent across multiple infectious diseases, suggesting it may serve as a biomarker and perhaps drug target for several deadly infectious diseases.
These findings could begin to impact the clinic rapidly, as clinicians may now specifically check OLAH expression to determine whether a patient will require more intensive treatment. However, there are currently no known, or at least reported OLAH inhibitors, meaning that a drug must be synthesized, then undergo years of preclinical testing before clinical trials could begin. In the meantime, dietary alterations may be considered, as well as other drugs that may indirectly reduce OLAH expression or activity.
Posted: 8/12/24
Science strikes back: PS757 enters the fight against antibiotic resistance
Antibiotic resistance, the ability of bacteria to survive antibiotic treatments, is associated with nearly 5 million deaths worldwide according to a 2019 report. To counter antibiotic resistance, new antibiotic compounds must be developed for clinical use. Recently, a group developed a potent compound, PS757, that is highly effective against a spectrum of gram-positive, a group of bacterial species that contribute to a wide array of human diseases.
A more recent study focused on PS757’s efficacy against Streptococcus pyogenes, which causes various skin and soft tissue infections, and is responsible for over 500,000 deaths per year. Most currently used antibiotics stop bacterial growth while bacteria are in what is known as the exponential growth phase. Unlike most antibiotics, PS757 is able to stop growth and kill S. pyogenes cells that are growing and finished growing. Further, PS757 can even penetrate and destroy biofilms formed by S. pyogenes cells, another feat most antibiotics are incapable of.
To progress to clinical trials, the safety and efficacy of a drug must be evaluated in non-human species. The authors tested the efficacy of PS757 in mice infected with S. pyogenes. Mice treated with PS757 were healthier, ulcers caused by infection were much smaller, and inflammation was reduced compared to untreated mice. Additionally, infected tissue healed much more rapidly in mice treated with PS757 compared to untreated animals. Lastly, gene expression analyses found that PS757 decreases the expression of disease-causing factors, possibly explaining its mechanism of action.
Overall, PS757 is a promising compound that has cleared many preclinical hurdles and would seem to be heading towards clinical trials in the near future. However, this study treated mice two hours after infection, which is almost certainly not going to be the case in humans. Future studies should test how treatment timing affects efficacy. Lastly, PS757 may have additive effects when paired with other antibiotics, as suggested by the initial report, which would be important for planning clinical trial strategies, especially in later stages.
Posted: 8/5/24
MTX-531: A new hope in the fight against cancer and adaptive resistance
The development of sequencing technology and highly specific anti-cancer drugs in recent years has allowed clinicians to specifically target cancer cells without harming non-cancer cells (precision medicine). However, like bacteria resisting antibiotics, cancer cells are also capable of evading anti-cancer drugs, a mechanism known as adaptive resistance. To combat adaptive resistance, patients are often treated with multiple drugs, each with different targets. Unfortunately, this approach comes with downsides, namely increased risk of off-target effects and negative drug interactions. Thus, the identification of a single drug that can successfully target multiple drivers of cancer and adaptive resistance would be of high clinical value.
A recent study published in Nature Cancer by Whitehead et al identified MTX-531 as a potent and highly selective inhibitor of two major drivers of cancer and adaptive resistance, EGFR and PI3K. Importantly, mouse models of a common and moderately lethal cancer, head and neck squamous cell carcinoma (HNSCC) treated with MTX-531 exhibited significantly longer lifespan and reduced tumor size compared to untreated animals. Excitingly, MTX-531 was even effective in late stage cancers. Furthermore, MTX-531 was well tolerated and hyperglycemia was not observed, like it is with other PI3K inhibitors. Overall, MTX-531 appears to be superior to other currently used EGFR and PI3K inhibitors.
Although MTX-531 was effective in mouse models of HNSCC, it remains unclear whether MTX-531 would work in other cancer models, or if it would be effective in humans. Additional experiments on mouse models of other types of cancer would be needed to test MTX-531’s efficacy against other cancers. Further, clinical trials would be the next step to test whether MTX-531 would be similarly effective in treating HNSCC in humans as it is in mice. If MTX-531 is effective against other cancers and its efficacy holds true in humans, this drug could transform cancer treatment plans and improve patient prognoses.
Butsch Science Communication 