Tagged: therapeutics

Reaching the Brain Through the Groin: A Novel Approach to Brain Cancer

In a new editorial, researchers discuss opening the blood-brain barrier and a promising new strategy for the treatment of brain cancer.

Figure 1: A transfemoral path to BBB opening.
Figure 1: A transfemoral path to BBB opening.

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Just a small number of molecules, including alcohol and caffeine, are able to cross the blood-brain barrier (BBB). The BBB is a highly selective semipermeable membrane that separates circulating blood from extracellular fluid in the brain. It plays a critical role in protecting the brain from harmful substances in the blood while also maintaining a stable and consistent environment for neuronal function. Without the BBB, humans would be at the mercy of any harmful toxin, pathogen and unwanted substance that could cross from the bloodstream into the brain.

This protective function also makes it difficult to deliver therapeutic agents to the brain, as the majority of drugs and other molecules are unable to cross the BBB. This is particularly problematic for the treatment of brain-localized diseases, including brain cancers and neurological disorders, which require high concentrations of drugs to effectively target sites in the brain. In a new editorial paper, researchers Thomas C. Chen, Weijun Wang and Axel H. Schönthal from the University of Southern California‘s Keck School of Medicine discuss a series of preclinical studies that introduced the novel concept of intraarterial (IA) injection of NEO100—a promising strategy aimed at temporarily and safely opening the BBB up for therapeutic treatment. Their editorial was published in Oncotarget’s Volume 14 on May 4, 2023, entitled, “From the groin to the brain: a transfemoral path to blood-brain barrier opening.”

“It is believed that procedures to open the BBB in a controlled and safe fashion might provide tremendous advantages by allowing optimal brain entry of any and all circulating therapeutics.”

Opening the BBB

The authors first describe previously used methods of opening the BBB for therapeutic intervention, including intracarotid injection of hyperosmolar mannitol and MRI-guided pFUS with intravascular microbubbles. Unfortunately, these methods have yielded issues with safety and efficacy. Fortunately, Chen, Wang, Schönthal, and their co-authors came up with a new idea for opening the BBB safely. 

In a 2021 study, the researchers discovered that NEO100 enables the delivery of BBB-impermeable therapeutics to the brain. NEO100 is a type of perillyl alcohol—a natural chemical found in citrus fruit peels—that has been studied for its potential to treat cancer. Wang et al. aimed to see if injecting NEO100 into an artery would open the BBB safely and temporarily. This could help other drugs that are normally unable to pass through the BBB, such as methotrexate and therapeutic antibodies, to enter the brain. Previously, NEO100 had been administered through the nose to treat cancer, but this study focused on its ability to open the BBB.

The researchers injected NEO100 into the left ventricle of the heart and then injected a dye called Evans blue into the mice’s veins. Normally, this dye cannot penetrate the brain, but when the BBB is weakened or opened up, it can get through and turn the brain blue. And that’s exactly what happened—the mice’s brains turned blue after the injections. Interestingly, when they tried using another substance called mannitol, it did not have the same effect on the BBB. The team performed additional studies and found that NEO100 seemed to affect the connections between cells in the barrier.

In further experiments, the researchers used methotrexate and special markers that usually do not enter the brain. They gave these drugs and markers to mice and found that NEO100 made it easier for the drugs and markers to enter the brain. This effect lasted between two and four hours before the BBB reverted to normal functioning. The researchers also tested administering NEO100 by injecting it into the mouse’s veins, but this was not effective. 

The main question the researchers wanted to answer was if opening the BBB using IA NEO100 could help treat brain tumors. To answer this question, they conducted experiments using mice that had tumor cells implanted in their brains. In one study, they used breast cancer cells that were engineered to have the protein HER2 and treated them with trastuzumab. In another study, they used models of brain cancer called melanoma and glioblastoma and treated them with drugs that help the immune system fight cancer. These studies have found a way to improve drug delivery for CNS diseases, but there are limitations that need further investigation.

Transfemoral IA catheterization

As noted in this editorial, the preclinical models above used one injection of NEO100 with a therapeutic agent, but it’s unclear if this will work as well in humans. Tumors in humans are more complex than in rodents, so multiple interventions might be needed. It is also important to determine the best way to perform the injection(s) in humans. The researchers suggest using a catheter inserted through the femoral artery near the groin and guided by fluoroscopy to safely inject NEO100 into the cranial arteries.

“Transfemoral IA catherization (Figure 1) is a low-risk procedure that is routinely performed by endovascular neurosurgeons in the context of cerebral angiograms, aneurysm coiling, tumor embolization, and thrombectomies [18]. It is considered ‘the gold standard technique for catheter-based neuro-interventions’ [19]. However, it has never been used as a means to access tumor-feeding cranial arteries for purposes of BBB opening.”

Transfemoral IA catheterization is a medical procedure that involves inserting a catheter through a blood vessel in the leg and guiding it to the brain to perform various treatments. It is a safe and common technique, already used by doctors who specialize in treating brain conditions. However, it has never been used to open the BBB in order to access the blood vessels. Using NEO100 with this procedure could be a new and innovative way to treat aggressive brain tumors. If necessary, the procedure could even be repeated multiple times due to its safe and simplistic nature. The researchers believe that using this new method to open the BBB could be just as successful in treating brain tumors as current treatments are for tumors in other parts of the body. This could potentially lead to better outcomes for patients with brain tumors, such as improved survival rates and fewer side effects.

Conclusions

The blood-brain barrier (BBB) is a protective barrier that prevents harmful substances from entering the brain. However, this barrier also makes it difficult to deliver therapeutic agents to the brain. In a new study, researchers have proposed a novel method of intraarterial injection of NEO100 to temporarily and safely open the BBB. This method has been shown to enable the delivery of BBB-impermeable therapeutics to the brain. The authors of this editorial have suggested using transfemoral IA catheterization to perform this intervention. The method requires further investigation and development.

“The authors envision that clinical implementation of this new BBB-opening method might achieve a similarly high rate of success in the treatment of brain-localized malignancies as do current treatments for peripherally distributed tumors; as a result, reduced morbidity and increased patient survival is expected.”

Click here to read the full editorial in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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Controlling Glycolytic Flux: Therapy Challenges and Solutions

In a new editorial paper, researchers from the University of Oxford explore challenges and potential solutions for controlling glycolytic flux by blocking lactate transporters in disease therapies.

Targeting Lactate Transporters for Disease Therapies

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The process of glycolysis, or the conversion of glucose to energy in cells, is a critical component of many biological processes. This process is highly regulated, and glycolytic flux has been implicated in a variety of disease states, including cancer and diabetes. Despite significant advances in our understanding of glycolysis, researchers continue to find it difficult to control glycolytic flux.

“Overall, glycolysis facilitates tumour proliferation and survival, and has become a hotly-pursued target for therapeutic inhibition.”

In a new editorial paper, researchers Wiktoria Blaszczak and Pawel Swietach from the University of Oxford explored the challenges of this issue and potential solutions. On January 26, 2023, their editorial was published in Oncotarget and entitled, “Permeability and driving force: why is it difficult to control glycolytic flux by blocking lactate transporters?

“In our recent study (Blaszczak et al. (2022)), using a panel of pancreatic ductal adenocarcinoma cell lines, we characterised how extracellular acidity feeds back to inhibit further glycolytic acid production [6].”

Blocking Lactate Transporters: Challenges

Lactate is produced as a byproduct of glycolysis. Lactate transporters are responsible for moving lactate out of cells. Blocking these transporters has long been thought of as a potential way to slow or stop glycolytic flux. However, as the authors of this editorial point out, attempts to do so have been met with limited success.

One of the key challenges in blocking lactate transporters is their complex regulation. These transporters are highly permeable to lactate, meaning that even small changes in their activity can have a significant impact on lactate flux. Additionally, lactate transporters are regulated by a variety of factors, including pH, ion concentrations and intracellular signaling pathways. This complexity makes it difficult to design drugs that selectively target lactate transporters without affecting other cellular processes.

Another challenge in blocking lactate transporters is the driving force that fuels lactate transport. The movement of lactate out of cells is driven by a concentration gradient, meaning that lactate moves from areas of high concentration to areas of low concentration. However, this gradient is often very small, meaning that even small changes in the activity of lactate transporters can have a significant impact on lactate flux. Additionally, lactate transporters are often coupled with other transporters, such as H+ transporters, which can further complicate efforts to block lactate transport.

Blocking Lactate Transporters: Solutions

Despite these challenges, the authors suggest that there may be ways to overcome them and better control glycolytic flux by targeting lactate transporters. One potential approach is to develop drugs that selectively target lactate transporters and are not affected by other cellular processes. This could be achieved by exploiting the structural differences between lactate transporters and other transporters. Additionally, targeting the intracellular signaling pathways that regulate lactate transporters could be a way to more selectively block lactate transport.

Another potential approach to controlling glycolytic flux is to target the driving force that fuels lactate transport. This could be achieved by altering the concentration gradient of lactate, either by blocking lactate production or by increasing lactate consumption. Additionally, targeting other transporters that are coupled with lactate transporters, such as H+ transporters, could be a way to indirectly control lactate transport and glycolytic flux.

“Overall, a decrease in permeability will increase driving force, thereby restoring flux.”

Conclusion

Overall, the researchers highlight the complex nature of lactate transport and the challenges that must be overcome to control glycolytic flux by blocking lactate transporters. Additionally, the authors suggest that there are potential solutions to these challenges and that continued research could lead to new insights into the regulation of glycolysis and the development of new therapies for diseases associated with alterations in glycolytic flux.

“Regardless of the chosen approach, it is likely that any successful therapeutic strategy for targeting glycolysis will be multifaceted to overcome some of the intricacies of complex pathways.”

Click here to read the full editorial published in Oncotarget

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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A New Method of Targeting Exosomes in Precision Medicine

Oncotarget published a new editorial perspective by Dr. Mujib Ullah, entitled, “The future of bioorthogonal-chemistry for targeting of exosomes in precision medicine.”

A New Method of Targeting Exosomes in Precision Medicine
Figure 1: Schematic illustration showing tracking of exosomes labeled by phospholipid-based bioorthogonal conjugation.
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Extracellular vesicles are membrane-bound vehicles released by cells into the extracellular environment. There are three known types of extracellular vesicles: microvesicles, apoptotic bodies and exosomes. Discovered in 1983, exosomes can be defined as packets of bio-nanoparticles released by cells containing bioactive molecules such as proteins, lipids and nucleic acids. Exosomes can deliver their payload to other cells and are now also recognized for their role in cell-to-cell communication. This makes exosomes attractive targets for precision medicine tactics. However, targeting exosomes is challenging due to their nano-size and reactive contents. Bioorthogonal-chemistry may provide a new approach for targeting exosomes in precision medicine.

“Bioorthogonal is the name of a chemical reaction that can occur inside of living cells without interfering the naïve biological process [1, 2].”

Bioorthogonal-chemistry allows for the attachment of bioactive molecules to the surface of exosomes without disturbing the native environment. Developed in the early 2000s, this strategy could potentially be used to deliver therapeutic drugs or bioactive molecules directly to the target site with high precision. Bioorthogonal-chemistry is still at an early stage of development, but it holds promise in precision medicine for the treatment of cancer and other illnesses. By providing a way to target exosomes with bioactive molecules, bioorthogonal-chemistry could help to significantly improve the efficacy of medical treatments. It could also reduce the side effects of current treatments and increase safety for patients.

“The concept of bioorthogonal chemistry has inspired a generation of biologists to think about RNA editing and bioengineering of exosomes [3, 4].”

On December 6, 2022, Oncotarget published a new editorial perspective by Dr. Mujib Ullah from Stanford University, entitled, “The future of bioorthogonal-chemistry for targeting of exosomes in precision medicine.”

In this short editorial perspective, Dr. Ullah discussed current exosome-loading techniques, including electroporation, heat shock, sonication, and ultracentrifugation. He wrote that these techniques are disruptive and potentially ineffective methods of exosome loading. On the other hand, he explained that using a precise, targeted bioorthogonal reaction can overcome the aforementioned issues. Dr. Ullah listed nine questions at the end of his editorial perspective. He believes these important questions must be answered in order to showcase the potential of bioorthogonal reactions in future clinical biomedical applications:

  1. Can bioorthogonal chemistry help in the development of more powerful bioimaging and biosensing techniques?
  2. Can the combination of exosomes with biorthogonal chemistry overcome some of the current translational hurdles in precision medicine?
  3. Can new drugs be designed inside humans?
  4. Can the exosomes cargo be detected by conjugation chemistry?
  5. Can we track the metabolites encapsulated inside the exosomes?
  6. Can pharmaceuticals be synthesized inside living system?
  7. How many orthogonal reactions can be performed in one time?
  8. What is the half life of these reactions?
  9. Biorthogonal reactions are rapid but what is the speed of reactions? 

Click here to read the full editorial perspective published by Oncotarget

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Trending With Impact: New Pre-Transplant AML Treatment Combinations

Researchers aimed to improve acute myeloid leukemia (AML) patient outcomes after allo-HSCT with new pre-transplant treatment combinations.

3D Illustration of acute myeloid leukemia

The Trending With Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Acute myeloid leukemia (AML) is a cancer of the blood that begins in the bone marrow and progresses quickly if left untreated. AML can occur both in adults and children and is often treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT is a procedure that replaces stem cells that were damaged or destroyed after radiation and/or chemotherapy treatment with stem cells from healthy donors. While allo-HSCT provides a high rate of curability in AML patients, the success of this procedure is partially dependent on the efficacy of pre-transplant treatment regimens. Researchers have identified an urgent need to determine new therapeutic approaches that provide better cytotoxicity in AML cells, without jeopardizing patient safety.

To improve AML patient outcomes after allo-HSCT, researchers fromthe University of Texas MD Anderson Cancer Center and the University of Alberta’s Cross Cancer Institute conducted a new study investigating the BCL-inhibitor ABT199/venetoclax in combination with two alkylating agents and a nucleoside analog. Their trending research paper was published by Oncotarget on February 10, 2022, and entitled, “ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells.”

“One such candidate drug is ABT199/venetoclax, a BH3-mimetic small molecule that binds to and inhibits the anti-apoptotic B-cell lymphoma 2 (BCL2) protein, preferentially causing malignant cells to undergo apoptosis [10].”

The Study

Previous studies have indicated cytotoxic properties among the alkylating agents busulfan (BU) and 4-hydroperoxycyclophosphamide (4HC), in the nucleoside analog fludarabine (Flu) and in the BCL2 inhibitor ABT199/venetoclax. The researchers in this study investigated the efficacy of ABT199/venetoclax when combined with [Bu+4HC] and [Bu+Flu] in three established AML cell lines: KBM3/Bu2506 (a Bu-resistant AML cell line established in the researchers’ laboratory), OCI-AML3 and MOLM14. They also isolated mononuclear cells taken from seven acute leukemia and myeloid dysplastic syndrome patients andexposed them to these drugs in order to assess their potential clinical implications.

“This study demonstrates a marked potentiation of the cytotoxicity of [Bu+4HC] and [Bu+Flu] when combined with the BCL2 inhibitor ABT199/venetoclax in the KBM3/Bu2506, OCI-AML3 and MOLM14 established AML cell lines.”

Study results showed that, individually, these drugs induced minimal drug-mediated apoptosis. The combination, however, of ABT199 with [Bu+4HC] or [Bu+Flu] exerted significant synergistic cytotoxicity towards AML cell lines. In the isolated mononuclear cells, a negative correlation was observed between the level of BCL2 protein and sensitivity to ABT199. The study found that the [Bu+4HC+ABT199] and [Bu+Flu+ABT199] drug combinations activated multiple biomarkers of apoptosis, increased CASPASE 3-mediated cleavage of MCL1 and MEK1/2, activated stress signaling pathways, and down-regulated pro-survival pathways.

“In summary, our results indicate strong antineoplastic activity of [Bu+4HC+ABT199] and [Bu+Flu+ABT199] towards AML cells.”

Conclusion

The combination of ABT199/venetoclax with alkylating agents and a nucleoside analog showed significant synergistic cytotoxicity towards AML cell lines in vitro. This study provides preclinical evidence for the clinical efficacy of these drug combinations and warrants further investigation in acute myeloid leukemia patients. The results of this study could lead to new, more effective treatment combinations for AML patients undergoing allo-HSCT.

“The results from this preclinical study may be used as the basis for clinical trials using [Bu+4HC+ABT199] or [Bu+Flu+ABT199] as pre-transplant conditioning therapy for high-risk AML patients undergoing allo-HSCT.”

Click here to read the full research paper published by Oncotarget.

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Scientific Integrity

Trending With Impact: Promising Non-Small Cell Lung Cancer Prodrug

Researchers examined the preclinical prodrug LP-184 and its efficacy in treating non-small cell lung cancers that lack actionable targets or resistance-related genes.

3D illustration of lung cancer

The Trending with Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Between 20 and 40% of adults with non-small cell lung cancer (NSCLC) eventually go on to develop brain metastases. Over 40% of patients with NSCLC have limited treatment options due to a lack of actionable therapeutic targets. Treatment for such patients has been limited to non-targeted chemotherapy—an approach which increases the risk of developing drug-resistance due to underlying resistance-associated mutations. 

“Newer drugs that will be more potent and remain efficacious in NSCLC with such mutations could lead to better alternate or combinatorial therapies.”

Lantern Pharma (a pharmaceutical company developing targeted cancer therapies) created a new drug candidate and next generation member of the acylfulvene class of prodrugs, named LP-184. Researchers from Lantern Pharma and REPROCELL (a commercial contract research organization) conducted a study to test the anti-tumor activity of this preclinical compound in a variety of NSCLC cell lines. In 2021, Oncotarget published team’s pape, entitled, “The acylfulvene alkylating agent, LP-184, retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy-refractory mutations.”

The Study

Despite LP-184’s highly-synthetic sounding name, the lead product in this acylfulvene prodrug (Illudins) is derived from, you guessed it, Jack-o-Lantern mushrooms. 

“Acylfulvenes have been derived from cytotoxic agents called Illudins, isolated from Jack-o-Lantern mushroom (Omphalotus illudens), that retain and improve the cytotoxicity of parent Illudins for use as anticancer agents.”

The anti-tumor activity of this compound is based on activation through reductive mechanisms, mediated by enzymes such as Prostaglandin Reductase 1 (PTGR1). PTGR1 is known to be upregulated in some tumors, including in tumors with mutations in KEAP1. LP-184 sensitivity was investigated in NSCLC cell lines with individual or combined mutations in KEAP1, KRAS, TP53, and STK11. 

“There is a high unmet need for effective therapies for NSCLC harboring mutations in these genes that have not only been considered undruggable till date but also are associated with loss of efficacy or resistance to multiple therapeutic strategies, at least in frontline regimens.”

The researchers tested LP-184 in vitro in 19 primary and metastatic NSCLC cell lines to determine the range of NSCLC settings that this compound might work best in. Clinical data analyses were also conducted by the researchers to predict tumor responsiveness to LP-184. In addition, the compound was examined in two mouse models of primary lung cancer. Mouse models were tested for sensitivity to LP-184 in both two- and three-dimensional culture systems.

“We sought to assess LP-184 activity in a panel of selected NSCLC adenocarcinoma cell lines, determine associations between genomic and transcriptomic profiles and responses of cell lines tested, and compare in vitro potency of LP-184 with that of approved chemotherapy agents.”

Conclusion

Among their many findings, the researchers demonstrated that LP-184 has high nanomolar potency in 11 of the 19 NSCLC cell lines tested—indicating broad NSCLC anti-tumor activity. In vivo, LP-184 showed efficacy in terms of tumor regression in one of the two mouse models.

“We propose further evaluation of LP-184 in multiple PTGR1 high NSCLC settings that may not necessarily be mutually exclusive, including in highly prevalent KEAP1 and KRAS mutant tumors (Figure 6), and in patients with lack of actionable targets or resistance-related genes with no effective therapy options available.”

Click here to read the full research paper, published by Oncotarget.

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