Tagged: Chemotherapy

Synergistic Effects of Drug Combinations Targeting AML Cells

April 11, 2024

In this new study, researchers investigated a promising new approach to acute myeloid leukemia (AML) therapy by combining multiple drugs to enhance cytotoxic effects on AML cells.

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Acute myeloid leukemia (AML) is a cancer characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. ABT199, also known as venetoclax, is a targeted therapy that inhibits the BCL-2 protein, which is often overexpressed in AML cells and contributes to their survival. By blocking this protein, venetoclax can trigger apoptosis, or programmed cell death, in cancer cells. Thiotepa, a DNA alkylating agent, has been used in conditioning regimens for hematopoietic stem cell transplantation (HSCT) but its combination with ABT199/venetoclax has not been thoroughly explored, until now.

In a new study, researchers Benigno C. Valdez, Bin Yuan, David Murray, Jeremy L. Ramdial, Uday Popat, Yago Nieto, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center and the University of Alberta investigated a promising new approach to AML therapy by combining multiple drugs to enhance cytotoxic effects on AML cells. On March 14, 2024, their new research paper was published in Oncotarget’s Volume 15, entitled, “ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells.”

“The results may provide relevant information for the design of clinical trials using these drugs to circumvent recognized drug-resistance mechanisms when used as part of pre-transplant conditioning regimens for AML patients undergoing allogenic HSCT.”

The Study

In this study, the researchers demonstrated a notable synergistic effect between ABT199/venetoclax and thiotepa, significantly amplifying cytotoxicity against AML cells. This effect was further magnified when these drugs were combined with fludarabine, cladribine, and busulfan, well-established chemotherapeutic agents renowned for their efficacy in AML treatment.

One pivotal discovery of the research lies in elucidating the molecular mechanism behind this heightened cytotoxicity. The combined drug regimen led to increased cleavage of Caspase 3, PARP1, and HSP90, recognized markers of apoptosis, indicative of a robust activation of the cell death pathway. Additionally, heightened Annexin V positivity, an indicator of early apoptosis stages, was observed, suggesting the effective initiation of cell death in AML cells.

The investigation also shed light on an augmented DNA damage response, evidenced by elevated levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19), and P-SMC1 (S957). These markers imply that the drug combination not only induces apoptosis but also contributes to the accumulation of DNA damage in AML cells, further fostering their demise.

Another significant outcome was the activation of stress signaling pathways, reflected in increased levels of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458). These alterations indicate cellular stress induced by drug treatment, potentially heightening sensitivity to the cytotoxic effects of the combination therapy.

Furthermore, the study addressed the pressing issue of drug resistance, commonly encountered in AML treatment. The five-drug combination notably decreased the levels of BCL-2, BCL-xL, and MCL-1, proteins associated with resistance to venetoclax, suggesting potential efficacy in overcoming resistance and improving treatment outcomes for AML patients. Various AML cell lines, including those with P53-negative and FLT3-ITD-positive mutations associated with poor prognosis, were subjected to the drug combination.

Results & Conclusion

The results exhibited promising activity of the combination therapy against these challenging cell lines. Moreover, extending the findings to clinical relevance, the drug combination was tested on leukemia patient-derived cell samples, revealing enhanced activation of apoptosis, which hints at potential effectiveness in a clinical setting and provides a basis for future clinical trials.

The implications of this research are profound, offering a novel strategy for conditioning regimens in AML patients undergoing HSCT. Combining ABT199/venetoclax and thiotepa with fludarabine, cladribine, and busulfan presents a promising approach for eradicating AML cells and preparing patients for stem cell transplantation. In conclusion, the study signifies a significant advancement in combating AML. The synergistic effects observed in combining ABT199/venetoclax with thiotepa and other chemotherapeutic agents pave the way for enhancing treatment regimens. This research sets the stage for future clinical trials and the potential development of more effective therapies for AML patients.

“The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.”

Click here to read the full research paper 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.

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Antitumor Effects of Sacituzumab Govitecan Plus Platinum-Based Chemotherapy

March 14, 2024

In this study, researchers investigated the antitumor effects of Sacituzumab govitecan in combination with platinum-based chemotherapy.

The relentless search for effective cancer therapies has led to numerous breakthroughs in drug discovery and development. Advancements have emerged in recent years through the promising avenue of combination therapy, where two or more drugs are used synergistically to enhance their collective therapeutic effect. This strategy has shown significant potential in overcoming drug resistance, reducing side effects, and improving patient survival rates.

In a new study, researchers Thomas M. Cardillo, Maria B. Zalath, Roberto Arrojo, Robert M. Sharkey, Serengulam V. Govindan, Chien-Hsing Chang, and David M. Goldenberg from Gilead Sciences and the Center for Molecular Medicine and Immunology demonstrated the significant antitumor effects of Sacituzumab govitecan, an anti-Trop-2-SN-38 antibody-drug conjugate, in combination with platinum-based chemotherapy. On February 22, 2024, their research paper was published in Oncotarget, entitled, “Sacituzumab govitecan plus platinum-based chemotherapy mediates significant antitumor effects in triple-negative breast, urinary bladder, and small-cell lung carcinomas.”

Sacituzumab Govitecan & Platinum-Based Chemotherapy

Sacituzumab govitecan is an innovative drug that has gained prominence in recent years due to its unique mechanism of action and remarkable antitumor effects. It is an antibody-drug conjugate composed of an anti-Trop-2-directed antibody linked with the topoisomerase I inhibitory drug, SN-38, via a proprietary hydrolysable linker. Trop-2 is a transmembrane glycoprotein that is highly expressed in various solid tumors, making it an attractive target for cancer therapy. SN-38, the active metabolite of the chemotherapy drug irinotecan, is a potent topoisomerase I inhibitor that triggers DNA damage and apoptosis in cancer cells.

Platinum-based chemotherapy, primarily cisplatin and carboplatin, is a cornerstone of cancer treatment. These drugs work by interfering with DNA replication in cancer cells, leading to cell death. However, their use is often limited by drug resistance and toxic side effects.

“Using multiple drugs to treat cancer may allow for direct activity against multiple targets simultaneously or may indirectly affect the same target through different mechanisms of action [16].”

The Study

The combination of Sacituzumab govitecan and platinum-based chemotherapy has the potential to overcome these limitations. In the current study, the researchers found this combination to produce significant antitumor effects in various cancer models, including triple-negative breast, urinary bladder, and small-cell lung carcinomas. They found that the combination treatment resulted in additive growth inhibitory effects in vitro. The combination led to significant down-regulation of anti-apoptotic proteins and up-regulation of pro-apoptotic proteins, suggesting a shift towards pro-apoptotic signaling.

The in vivo efficacy of the combination therapy was further confirmed in mice bearing human tumor xenografts. The combination of Sacituzumab govitecan and carboplatin or cisplatin resulted in significant tumor regressions in all tested models. Importantly, the combination therapy was well tolerated by the animals, indicating a favorable safety profile.

Conclusions

The findings from this study represent a significant leap forward in the field of chemotherapy combination therapy drug discovery. The team provided strong evidence to support the clinical investigation of Sacituzumab govitecan in combination with platinum-based chemotherapy for the treatment of various solid tumors. Future studies should investigate the optimal dosing and sequencing of this combination therapy to maximize its efficacy and minimize potential toxicities. Additionally, the exploration of potential biomarkers could help identify patients who are most likely to benefit from this combination therapy.

In summary, the combination of Sacituzumab govitecan (SG) and platinum-based chemotherapy holds great promise as a potent antitumor therapy. It represents a novel approach that could potentially revolutionize the treatment of various solid tumors and improve patient outcomes.

“Importantly, these data demonstrate significantly greater antitumor effects of SG plus carboplatin or cisplatin in tumor-bearing mice than monotherapies, and that they were well tolerated by the animals. Based on these results, SG plus platinum-based chemotherapeutics merit clinical investigation.”

Click here to read the full research paper in Oncotarget.

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

May 11, 2023

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.

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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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Targeting Pre-Leukemic Cells: New Hope for Preventing Childhood B-ALL

March 31, 2023

Researchers from Universidad Autónoma de Madrid published a new editorial in Oncotarget detailing a proof-of-principle experiment to prevent B-cell acute lymphoblastic leukemia (B-ALL).

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Childhood leukemia is a devastating disease that affects thousands of children every year. Despite significant advancements in the field of pediatric oncology, childhood leukemia remains a major cause of morbidity and mortality in children, with B-cell acute lymphoblastic leukemia (B-ALL) being the most common form.

Some cases of childhood B-ALL arise from congenital mutations that lead to a silent population of pre-leukemic cells. These cells at some point are triggered by a catalyst (possibly by delayed exposure to a common infection), acquire additional genetic mutations and ultimately develop into B-ALL. However, researchers have yet to fully understand how to target these pre-leukemic cells to prevent B-ALL.

In a new editorial paper, researchers César Cobaleda, Manuel Ramírez-Orellana, Carolina Vicente-Dueñas, Andreas Weiss, Kim E. Nichols, and Isidro Sánchez-García from Universidad Autónoma de Madrid discuss a novel method of targeting pre-leukemic cells in practice. On March 11, 2023, the team published their editorial in Oncotarget, entitled, “Proof-of-principle: targeted childhood leukemia prevention.”

“[…] one would have to find a way to specifically target these preleukemic cells. Recently, a mouse model recapitulating the phenotype of a leukemia-predisposition syndrome has allowed us to carry out a proof-of-principle experiment to achieve this very goal.”

The Study

Pax5 is a protein that plays a critical role in the development of white blood cells that produce antibodies to fight infections, B cells. A Pax5 mutation or deficiency can lead to a disruption in the development of B cells and compromise the immune system’s ability to fight off infections. Pax5+/- refers to an individual or organism that has one functional copy of the Pax5 gene and one non-functional copy. This condition is also known as heterozygosity.

“Children carrying heterozygous mutations affecting the B-cell master regulator gene PAX5 are predisposed to develop B-ALL; similarly, 25% of heterozygous Pax5+/− mice develop leukemia, but only after experiencing an immune stress, such as exposure to infection [2–4].”

In their recent study, the researchers used Pax5+/− mice (a mouse model carrying a leukemia-predisposition syndrome) to evaluate whether in vivo treatment with ruxolitinib, a Jak1/2 inhibitor, administered early in life is capable of killing pre-leukemic cells and preventing the development of acute leukemia. They found that treatment with ruxolitinib led to the disappearance of B-cell progenitors in Pax5+/-, but not in wild-type (WT), mice. When both experimental Pax5+/- and control WT animals were fed with ruxolitinib-containing chow for 14 or 28 days and then exposed to common mouse pathogens, the animals treated with ruxolitinib for 28 days showed a significant 90% reduction in the incidence of B-ALL compared to untreated mice or animals treated only for 14 days.

Ultra-deep sequencing studies of Pax5+/- mice showed that ruxolitinib acts by eliminating predisposed preleukemic B cells before the second “hit” (or catalyst) that leads to their descent into B-ALL. These findings suggest that an analogous approach could be used to prevent the development of B-ALL in children who carry germline mutations that predispose them to this disease.

“It is becoming increasingly clear that the existence of latent pretumoral cells is common to many types of both hematologic and solid cancers [7]; therefore, the concept described here could be considered a proof-of-principle strategy for the development of similar prophylactic approaches to prevent the progression of other malignancies.”

Figure 1: Targeted prevention of progression to B-ALL.

Summary & Conclusion

Childhood leukemia, specifically B-cell acute lymphoblastic leukemia, remains a significant cause of morbidity and mortality in children, despite advancements in pediatric oncology. The pre-leukemic cells that predispose children to B-ALL are not fully understood, making it challenging to prevent the disease. However, the recent study by Cobaleda C, et al. offers new hope. The proof-of-principle experiment demonstrates that early treatment with ruxolitinib can eliminate pre-leukemic cells and significantly reduce the incidence of B-ALL in the Pax5+/- mouse model.

Their findings suggest that a similar approach could be used to prevent B-ALL in children with germline mutations that predispose them to this disease. The concept described in this study could also serve as a strategy for developing prophylactic approaches to prevent the progression of other malignancies that share the existence of latent pretumoral cells. While further research is necessary, this study offers new possibilities in preventing childhood leukemia and improving the outcomes for children at risk.

“Still, some aspects remain unclear. For example, why do the majority of genetically predisposed animals (and most genetically predisposed children) not develop leukemia and stay healthy? In addition, what are the mechanisms by which environmental factors such as infection promote the acquisition of secondary mutations leading to malignant progression of preleukemic cells? These and other important questions still need to be answered if we are to fully understand and avert the appearance of B-ALL.”

Click here to read the full editorial published in Oncotarget.

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The Role of Kras and Canonical Wnt Pathways in Biliary Tract Cancers

March 1, 2023

In a recent Oncotarget editorial, researchers discuss Kras and the canonical Wnt pathway in biliary tract cancers, and potential theraputic strategies using these targets.

Figure 1: The role of Kras and canonical Wnt pathways for tumorigenesis of extrahepatic biliary system.

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The extrahepatic biliary system is a network of tubes and ducts that carry bile from the liver to the small intestine, where it helps digest fats. Biliary tract cancers, including gallbladder cancer and cholangiocarcinoma, are rare but aggressive cancers that arise from this system. Understanding the molecular mechanisms that drive these cancers is crucial for developing effective therapies.

“Despite advances in diagnosis and therapy, 5-year survival rate of biliary cancer is only 5% to 15% [7, 8].”

In a new editorial, researchers Munemasa Nagao, Akihisa Fukuda and Hiroshi Seno from Kyoto University Graduate School of Medicine discuss the latest research on the role of Kras and the canonical Wnt pathway in the development of biliary tract cancers. On January 26, 2023, their paper was published in Oncotarget’s Volume 14, entitled, “The role of Kras and canonical Wnt pathways for tumorigenesis of extrahepatic biliary system.”

Kras and The Canonical Wnt Pathway in Biliary Tract Cancers

Kras is a gene that plays a key role in regulating cell growth and division. Mutations in Kras are common in many types of cancer, including biliary tract cancers. The authors of this editorial note that recent studies have shown that Kras mutations are relatively frequent in biliary cancers. These mutations activate the Kras protein, leading to uncontrolled cell growth and division.

The canonical Wnt pathway is another molecular pathway that has been implicated in cancer development. The Wnt pathway helps regulate cell growth and division during embryonic development and in adult tissues. Abnormal activation of the Wnt pathway has been linked to several types of cancer, including colon cancer and liver cancer. Recent studies have shown that the canonical Wnt pathway is also activated in biliary tract cancers.

“However, the role of the KRAS and WNT pathways in biliary tumorigenesis remained unclear.”

A protein called beta-catenin, which is a key component of the Wnt pathway, is often overexpressed in biliary tract cancers. This leads to the activation of downstream target genes that promote cell growth and division. The researchers also discussed results from their 2022 study investigating the role of the Kras and canonical Wnt pathways in the tumorigenesis of the extrahepatic biliary system using a genetically engineered mouse (GEM) model.

“In summary, concurrent activation of the Kras and Wnt pathways in the extrahepatic biliary system induced ICPN and BilIN, which can progress to biliary cancer (Figure 1). This study provides the first novel GEM that recapitulates human ICPN and BilIN, establishing them precancerous lesions. This work shows how dysregulation of canonical cell growth pathways drives precursors to biliary cancers and identifies several molecular vulnerabilities as potential therapeutic targets in these precursors to prevent oncogenic progression.”

Potential Therapeutic Strategies for Biliary Tract Cancers

The researchers go on to discuss the concurrent activation, or crosstalk, between Kras and these pathways in biliary tract cancers. They note that several studies have shown that Kras mutations can activate the Wnt pathway, leading to even more aggressive cancer growth. This suggests that targeting both pathways may be necessary for effective therapy.

Potential therapeutic strategies targeting Kras and Wnt pathways in biliary tract cancers were discussed in this editorial. Several drugs that target these pathways are currently in development, and some are already being tested in clinical trials. The authors suggest that combining these drugs with chemotherapy or other targeted therapies may be a promising approach for treating biliary tract cancers.

“To develop novel preventive and therapeutic approaches for extrahepatic biliary cancer, it is also important to clarify the role of other altered genes by using a GEM model and/or human samples.”

Conclusion

Overall, this editorial provides a comprehensive overview of the latest research on the molecular mechanisms underlying biliary tract cancers. Their discussion of the role of Kras and the canonical Wnt pathway highlights the importance of understanding these pathways for developing effective therapies. The potential for combination therapies targeting both Kras and the canonical Wnt pathway is particularly intriguing, and could offer new hope for patients with these aggressive cancers.

Withstanding, it is important to note that more research is needed before these ideas can be translated into clinical practice. The authors themselves acknowledge that the development of effective targeted therapies for biliary tract cancers is still in its early stages. However, with continued research and collaboration, it is possible that new treatments will emerge that can improve the prognosis for patients with these challenging cancers.

Click here to read the full editorial published in Oncotarget.

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Novel Antibody Drug Conjugate Improves Murine Acute Myeloid Leukemia

January 4, 2023

Researchers from Astellas Pharma Inc. investigated the efficacy of a novel antibody drug conjugate combined with venetoclax and azacitidine in a mouse model of acute myeloid leukemia.

Novel Antibody Drug Conjugate Improves Murine Acute Myeloid Leukemia

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The average age of patients with acute myeloid leukemia (AML) is 67 years old. Older adults generally have a lower tolerance for treatments that exhibit high off-target toxicity. Additionally, chemotherapy-relapsed or -refractory (R/R) AML patients are often at an advanced stage of disease and are therefore more likely to have comorbidities that may reduce their tolerance for harsh treatments.

Thus, pharmaceutical AML drugs with high efficacy and low toxicity are in high demand. Antibody drug conjugates (ADCs) are emerging as promising therapeutic approaches to more safely treat hematological malignancies by reducing side effects. ADCs are designed to decrease damage to healthy tissues by specifically targeting tumor-associated antigens attached to cancer cells.

“Antibody drug conjugates (ADC) are one of the modalities that aims to dissociate drug efficacy from toxicity. ADC consists of three components: antibody specific for tumor associated antigen, drug linker and cytotoxic payload.”

Astellas Pharma

Recently, researchers from Astellas Pharma Inc. (a pharmaceutical company in Japan) developed ASP1235—a novel ADC that targets Fms-like tyrosine kinase 3 (FLT3). In more than 90% of AML patients, FLT3 is overexpressed on leukemic blasts. ASP1235 is designed to target FLT3-positive leukemia cells and deliver the cytotoxic drug payload to these cells. However, this drug alone was found to have only a mild effect on AML cells, prompting researchers to assess the efficacy of ASP1235 in combination with other drugs.

In a new study, Astellas Pharma researchers Hirofumi Tsuzuki, Tatsuya Kawase, Taisuke Nakazawa, Masamichi Mori, and Taku Yoshida investigated the efficacy of ASP1235 combined with venetoclax (an anti-apoptotic agent) and azacitidine (a DNA methyltransferase inhibitor) in an experimental mouse model of AML. Their research paper was published in Oncotarget on December 20, 2022, and entitled, “Anti-tumor effect of antibody drug conjugate ASP1235 targeting Fms-like tyrosine kinase 3 with venetoclax plus azacitidine in an acute myeloid leukemia xenograft mouse model.”

“In this study, we sought to evaluate the therapeutic effect of ASP1235 in combination with venetoclax plus azacitidine, a novel standard-of-care treatment for elderly AML patients, in ASP1235 poor sensitive AML cells.”

The Study

The researchers first aimed to determine an AML cell line that was only partially sensitive to ASP1235 monotherapy. They determined the THP-1 cell line was appropriate for further investigation. They compared FLT3 and Bcl-2 expression levels in THP-1 cells with primary leukemic cells from chemotherapy R/R AML patients to consider the clinical relevance of each. In THP-1 cells, the expression levels of FLT3 and Bcl-2 were found to be clinically relevant.

“It has been reported that the proportion of patients showing high Bcl-2 expression was greater in chemotherapy R/R AML patients compared to that in newly diagnosed patients [4]. Thus, we investigated the expression levels of Bcl-2 together with FLT3 to further consider the relevance of THP-1 cells for evaluation on the combination treatment with venetoclax.”

To confirm their in vitro findings, they used a THP-1 xenograft mouse model for in vivo investigation of ASP1235 sensitivity. Their findings indicated that the THP-1 cell was a partially sensitive preclinical model to ASP1235. Next, the researchers evaluated the in vivo efficacy of ASP1235 in combination with venetoclax plus azacitidine using the THP-1 xenograft mouse model. The results showed that the combination therapy induced a significant reduction in tumor size compared to ASP1235 monotherapy and the other two drugs alone. This suggests that ASP1235 has an enhanced anti-tumor effect in combination with venetoclax and azacitidine.

“Consistent with in vitro observations in Figure 4, triple combination treatment with ASP1235, venetoclax and azacitidine induced tumor regression, and the anti-tumor effect of the triple combination was much stronger than that of ASP1235 single agent or venetoclax plus azacitidine without obvious body weight loss (Figure 5).”

Figure 5: ASP1235 showed enhanced anti-tumor effect in combination with venetoclax and azacitidine in THP-1 xenograft mouse model.

Conclusions

The findings of this study suggest that the combination therapy of ASP1235, venetoclax and azacitidine can be an effective treatment option for elderly patients or patients with chemotherapy R/R AML. This combination therapy induced a significant reduction in xenograft tumors in the THP-1 mouse model, suggesting that it may be a promising therapeutic approach for AML patients. Further clinical trials are needed to confirm these results.

“In conclusion, the triple combination treatment of ASP1235, venetoclax and azacitidine has the potential to benefit AML patients, and there is a possibility to expect the combination effect of ASP1235 and venetoclax regimen in FLT3 positive cancers beyond AML.”

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

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Biomarkers May Predict Neoadjuvant Chemosensitivity in Bladder Cancer

November 15, 2022

In a new study, researchers aimed to identify and validate predictive biomarkers of response to neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC).

Biomarkers May Predict Neoadjuvant Chemosensitivity in Bladder Cancer

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Neoadjuvant chemotherapy (NAC) is a type of cancer treatment involving the administration of chemotherapy drugs before surgery. The goal of NAC is to shrink the tumor(s) in order to make it/them easier to remove during surgery and to decrease the chance of cancer recurrence after treatment. NAC is typically well tolerated by patients and has been shown to improve outcomes in patients with bladder cancer.

Predictive biomarkers are being increasingly used in oncology to identify patients who are likely to respond to chemotherapy. In the past, the decision to administer chemotherapy was based on tumor type and stage. However, it is now understood that there is considerable heterogeneity within these groups, and that not all patients will respond to the same treatment. Predictive biomarkers can help to overcome this challenge by identifying those patients who are most likely to benefit from chemotherapy.

There are a number of different types of predictive biomarkers, which can be divided into two broad categories: tumor biomarkers and host biomarkers. Tumor biomarkers are usually specific to the tumor type and can include markers of cell proliferation and DNA repair. Host biomarkers are usually found in the blood or other bodily fluids and can include markers of inflammation, immune function and metabolism. The use of predictive biomarkers has the potential to improve the efficacy of chemotherapy and reduce toxicity by avoiding its use in patients who are unlikely to benefit.

The Study

In a new study, researchers Neal Murphy, Andrew J. Shih, Paras Shah, Oksana Yaskiv, Houman Khalili, Anthony Liew, Annette T. Lee, and Xin-Hua Zhu from Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Northwell Health Cancer Institute, Feinstein Institutes for Medical Research, and Mayo Clinic aimed to develop and validate a predictive biomarker panel for response to NAC in patients with muscle-invasive bladder cancer (MIBC). Their research paper was published on November 2, 2022, in Oncotarget’s Volume 13, entitled, “Predictive molecular biomarkers for determining neoadjuvant chemosensitivity in muscle invasive bladder cancer.”

“The NAC non-responders suffer from unnecessary adverse effects and a delay in time to cystectomy leading to worse overall survival [9, 10]. Subsequently, there remains a critical need to understand the molecular biology behind NAC responsiveness, in order to better tailor individual NAC therapy.”

The purpose of this research was to “develop a molecular signature that can identify MIBC NAC responders (R) and non-responders (NR) using a cohort of known NAC response phenotypes, and better understand differences in molecular pathways and subtype classifications between NAC R and NR.” Researchers identified a total of 26 patients with known NAC response for inclusion in this study. These patients were assigned at random to either the discovery or validation cohort. The discovery cohort consisted of seven NAC responders and 11 non-responders. The validation cohort consisted of three responders and five non-responders.

Transurethral resection of bladder tumor (TURBT) specimens from the Northwell Health pathology department were received as formalin-fixed, paraffin-embedded (FFPE) tissue blocks. Pathologic response was determined at the time of cystectomy. Messenger RNA (mRNA) and microRNA (miRNA) from the FFPE blocks were sequenced using RNAseq and qPCR, respectively.

“To our knowledge, our study is the first to use combined differential mRNA and miRNA expression in MIBC to identify a NAC response signature.”

The Results

“We report significant gene sets associated with NAC response phenotype, as well as three multigene and miRNA signatures generated by CCA that can be used to potentially classify NAC response.”

In the discovery cohort, the researchers found that 2309 genes were differentially expressed between the NAC responders and non-responders. In the validation cohort, 602 genes and 13 miRNA were differentially expressed. Canonical correlation (CC) analysis found that three CCs (CC13: nucleoside triphosphate metabolic process; CC16: cell cycle and cellular response to DNA damage; and CC17: DNA packaging complex) were differentiated in the discovery and validation datasets. As far as MIBC subtypes, the MD Anderson p53-like subtype, CIT MC4 subtype and Consensus Class stroma-rich subtype had the strongest correlation with a non-responder phenotype. There were no subtypes that had strong correlations with the responder phenotype.

“In conclusion, our results identify molecular signatures that can be used to differentiate MIBC NAC responders versus non-responders. We have presented the salient molecular pathways and relevant genes, including mitochondrial response gene expression (MRPS12, MRPS34, MRPS28, MRPS14, and MRPS2), DNA replication initiation, and DNA unwinding and DNA damage (MCM2-3, MCM5-6 and XAP , ELK4, and FOXA3) that can be further analyzed to better understand NAC response. The above mentioned genes derived from their respective three pathways may be selected as part of a NAC response biomarker panel. In addition, we have highlighted the utility of molecular subtyping in relation to NAC response. If validated in a larger cohort, these findings may help deliver chemotherapy to those patients most likely to respond.”

Conclusion

Neoadjuvant chemotherapy is a promising treatment option for muscle-invasive bladder cancer patients, however, there is a class of patients who do not respond to chemotherapy. The results of this study implicate several different types of biomarkers that may be associated with chemosensitivity in MIBC patients. Further research is needed to validate these findings. Ultimately, if validated, these biomarkers could help to spare non-responders from side effects associated with ineffective and unnecessary chemotherapy.

“Our results identify molecular signatures that can be used to differentiate MIBC NAC R versus NR, salient molecular pathway differences, and highlight the utility of molecular subtyping in relation to NAC response.”

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

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Oncotarget

Synergy of HDACi, PARPi and Chemotherapeutics Against Blood Cancer

October 19, 2022

Researchers investigated the efficacy of HDAC inhibitors in combination with PARP inhibitors and chemotherapeutic drugs in multiple blood cancer cell lines.

Synergy of HDACi, PARPi and Chemotherapeutics Against Blood Cancer

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Chromatin constitutes chromosomes in eukaryotic cells and comprises DNA and proteins. Chromosomes produce proteins and enzymes that are essential for cellular function and maintenance, including DNA repair. A critical process for DNA repair is poly(ADP-ribosyl)ation, or PARylation.

PARylation is triggered by poly(ADP ribose) polymerase (PARP) enzymes. When DNA becomes damaged, PARP enzymes bind to the damaged location in the cell. In cancer cells, however, this natural process can be counterproductive in respect to cancer treatment. PARylation can produce DNA repair mechanisms in cancer cells that can lead to cell death evasion and even drug resistance. Inhibiting PARylation may be a viable therapeutic strategy for cancer treatment.

HDAC Inhibitors

Histones, the main proteins that constitute chromatin, undergo post-translational modifications that regulate gene expression. Histone acetylation is an important epigenetic process that affects gene expression by relaxing the chromatin structure, making chromatin remodeling more feasible. Histone deacetylases (HDACs) are enzymes that can have the opposite effect. Histone deacetylation makes the chromatin more compact and difficult to remodel. The overexpression of HDAC has also been associated with tumorigenesis. Histone deacetylase inhibitors (HDACi) are a class of therapeutics that have shown promise in the treatment of hematologic malignancies (blood cancer) and solid tumors.

“Overexpression of HDACs has been associated with tumorigenesis by down-regulation of tumor suppressor genes [3, 4]; hence, HDAC inhibitors (HDACi) including vorinostat (SAHA), romidepsin (Rom), panobinostat (Pano) and belinostat have been approved by the United States Food and Drug Administration for the treatment of hematologic and other malignancies [5]. These inhibitors restore appropriate gene expression, resulting in induction of cell differentiation, cell cycle arrest and apoptosis [6].”

The Study

In a new study, researchers Benigno C. Valdez, Yago Nieto, Bin Yuan, David Murray, and Borje S. Andersson from the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center and the Cross Cancer Institute’s Department of Experimental Oncology at the University of Alberta investigate the efficacy of HDACi in combination with PARP inhibitors (PARPi) and chemotherapeutic drugs to treat hematologic cancer. On October 14, 2022, their research paper was published in Volume 13 of Oncotarget, entitled, “HDAC inhibitors suppress protein poly(ADP-ribosyl)ation and DNA repair protein levels and phosphorylation status in hematologic cancer cells: implications for their use in combination with PARP inhibitors and chemotherapeutic drugs.”

“Despite their preclinical efficacy, HDACi do not seem to be clinically highly effective as monotherapy, and potentially more effective anti-tumor activity is observed when they are combined with other anti-cancer drugs [7–9].”

Studies on the interactions of HDACi with PARPi in cancers of the blood are limited, especially when combined with chemotherapeutic agents. The researchers used a panel of hematologic cancer cell lines (acute myeloid leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, and multiple myeloma) and patient-derived cell samples to study the effect of HDACi (including SAHA (Vorinostat), panobinostat (Pano), romidepsin (Rom) and trichostatin A (TSA)) on PARylation. In addition, the team looked at the efficacy of HDACi combined with PARPi, including Olaparib (Ola) and niraparib (Npb), and with chemotherapeutic agents gemcitabine (Gem), busulfan (Bu) and melphalan (Mel).

Results

The researchers found that hematologic cancer cell lines and patient-derived cell samples exposed to various HDACi resulted in a significant caspase-independent inhibition of protein PARylation. HDACi-mediated inhibition of protein PARylation was mainly catalyzed by PARP1. These findings suggest that HDACi could potentially be used in combination with PARP inhibitors and chemotherapeutic drugs to treat blood cancers.

“Our results indicate that the anti-tumor efficacy of HDACi is partly due to down-regulation of PARylation, which negatively affects the status of DNA repair proteins. This repair inhibition, combined with the high levels of oxidative and DNA replication stress characteristic of cancer cells, could have conferred these hematologic cancer cells not only with a high sensitivity to HDACi but also with a heightened dependence on PARP and therefore with extreme sensitivity to combined HDACi/PARPi treatment and, by extension, to their combination with conventional DNA-damaging chemotherapeutic agents. The observed synergism of these drugs could have a major significance in improving treatment of these cancers.”

Conclusion

HDACi drugs can inhibit PARylation. The combination of HDACi-mediated inhibition of PARylation was complemented by PARPi and chemotherapeutic agents in multiple blood cancer cell lines. The efficacy of this combined treatment was superior to that of any single agent, supporting the further clinical development of HDACi in cancer therapy. These findings could potentially be used to improve the treatment of hematologic cancers.

“In conclusion, our results provide a molecular explanation for the HDACi-mediated inhibition of DNA repair in hematologic cancer cells and support the combinatorial application of HDACi, PARPi and chemotherapeutic agents for the treatment of hematologic malignancies.”

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

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Oncotarget

Trending With Impact: Are NOTCH1 Variants Prognostic in Breast Cancer?

February 24, 2022

Researchers determined the prognostic ability of three NOTCH1 gene variants by incorporating them into two non-tumorigenic breast cell lines.

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The genetic changes that occur within the protein-coding gene NOTCH1 have not yet been fully studied or classified. Despite a lack in research, previous studies have suggested that NOTCH1 may be a potential target for novel cancer therapies, particularly against triple-negative breast cancer (TNBC). NOTCH1 variants in TNBC tend to cluster in the PEST region and have previously been linked to gamma secretase inhibitor (GSI) sensitivity and chemotherapy resistance.

“Furthermore, TNBC patients with increased Notch1 expression have demonstrated increased aggressive phenotypes and lower median overall survival [25].”

Since TNBC is well-known for a lack of actionable therapeutic targets, aggressive phenotypes and poor prognoses, there is an important need to develop new targeted therapies—as well as predictive markers for those therapies. Researchers from The Johns Hopkins University School of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center experimented in vitro with NOTCH1 variants and their ability to predict TNBC responsiveness to GSIs and standard of care chemotherapies. Their trending research paper was published by Oncotarget on February 16, 2022, and entitled, “NOTCH1 PEST domain variants are responsive to standard of care treatments despite distinct transformative properties in a breast cancer model.”

The Study

The researchers used three publicly available tumor-associated variant databases to identify three NOTCH1 variants that are commonly mutated in breast cancers; two variants were located in the A2441 site on NOTCH1 and the third variant was located in the PEST region of NOTCH1. To investigate the role of these NOTCH1 variants in TNBC in vitro, the team cultured two non-tumorigenic breast epithelial cell lines. Uniquely, they used an adeno-associated virus (AAV) vector to isogenically incorporate the NOTCH1 variants into the two cell lines. The researchers also developed a wildtype vector for the control arm of the study.

“In addition to the NOTCH1 variants, a targeted wildtype (TWT), which underwent the same gene targeting mechanism with a wildtype vector, was generated for both parental cell lines to act as a control.”

A standard growth factor supplemented media was used to determine if the NOTCH1 variants caused increased proliferation in the non-tumorigenic cell lines. Compared to the controls, no significant change in proliferation was observed. They also removed the epidermal growth factor (EGF) from the cells to determine if these NOTCH1 variants impart a ligand-independent proliferative advantage. In both cell lines, their results demonstrated that the A2441 variants exhibited EGF-independent growth, while the PEST NOTCH1 variant did not. Immunoblot analyses suggested that, in the absence of EGF, the A2441 NOTCH1 variants activated the MAPK pathway. These EGF-independent NOTCH1 variants (not the PEST NOTCH1 variant) conferred an invasive growth phenotype, increased migratory potential, had dysregulated 3D morphology, and significantly altered gene expression in cancer pathway genes.

Next, to measure the responsiveness and susceptibility of these variants to therapeutic agents, the cells were treated with six chemotherapeutic agents and nirogacestat—a GSI drug. Interestingly, none of the three variants demonstrated significantly different responses to the treatments when compared to one another. Furthermore, all of the variants showed sensitivity to these standard therapies used against TNBC. This suggests that these specific genetic changes within NOTCH do not have a large impact on tumor behavior and may not be useful as predictive markers for therapy response.

Conclusion

“Taken together, these data suggest that the oncogenic potential of NOTCH1 PEST domain variants depends on both variant type and amino acid location.”

Contrary to previous studies, the researchers found that the three NOTCH variants did not demonstrate significantly different responses to the GSI or the chemotherapies despite demonstrating distinct phenotypes. The lack of differential responses demonstrated by the variants in this study suggests that there is high variability among NOTCH1 variants. The prognostic potential of NOTCH1 may be dependent on the type of variant and its location, but more expansive research is necessary.

“Future studies involving meticulous characterization of an expansive panel of NOTCH1 variants in a similar model may provide mechanistic insight and predictive and/or prognostic value that is both variant type and site dependent.”

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

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Oncotarget

What Causes Chemo Brain?

February 2, 2022

Researchers investigated potential therapeutic culprits of “chemo brain” in a trending new paper published by Oncotarget.

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A type of mental fog—known as “chemo brain”—is widely experienced by patients who have undergone cancer treatment. Cancer research institutions define chemo brain as impaired cognition, including cloudiness, memory loss and/or lack of concentration, that occurs before, during and/or after cancer treatment. This condition can negatively impact quality of life in a significant way. Chemo brain not only affects recovering individuals but also their loved ones, who often must take on additional caregiving responsibilities. Despite the name, chemotherapeutic drugs may not be the only treatments responsible for chemo brain.

A chemotherapy protective drug called amifostine is commonly used in patients and paired with chemotherapeutic agents. Amifostine functions to protect healthy cells from DNA double strand breaks (DSBs) induced by chemotherapy. Another commonly prescribed cancer treatment is called etoposide, which is a chemotherapeutic drug that also targets DSBs. Etoposide, on the other hand, functions to increase DSBs in cancer cells. Recently, researchers have suggested that DSBs could play a role in learning, memory and immediate early gene (IEG) expression. The activity of IEGs can be used to identify neural circuits involved in learning and memory processes.

“Despite their wide clinical use, there is little information about how amifostine and etoposide affect learning and memory.”

THE STUDY

Researchers from Oregon Health and Science University conducted a novel study to observe the isolated effects of these common DSB-altering agents on learning, memory and IEG expression. Systemic injections of amifostine and etoposide were examined in both male and female mice. Their research paper was published by Oncotarget in January of 2022, and entitled, “Common cancer treatments targeting DNA double strand breaks affect long-term memory and relate to immediate early gene expression in a sex-dependent manner.”

“In this study, we investigated the effects of amifostine and etoposide on hippocampus-dependent and -independent fear conditioning [23] and IEG expression in male and female C57Bl/6J mice.”

Male and female mice were systemically dosed with either saline or the one of the cancer treatments, and then trained in fear conditioning. Markers of contextual and cued memory were tested 24 hours and two weeks post-training. The study consisted of four total experiments. The first experiment examined the effects of pre-training cancer treatment injections on long-term memory. The second experiment examined the effects of post-training cancer treatment injections on long-term memory. The third experiment examined the effects of pre-training injections on cFos and Nicotinamide adenine dinucleotide phosphate (NADPH). (Increasing and inhibiting the activity of NADPH oxidase impairs learning and memory.) The fourth experiment examined the effects of pre-training cancer treatment injections on DSBs.

“Hippocampal cFos and ΔFosB are essential for contextual learning and hippocampal synaptic plasticity [12, 13].”

RESULTS

The researchers found that pre- and post-training injections of amifostine at 107 mg/kg increased long-term contextual, but not cued, freezing in male mice. Amifostine decreased hippocampal DSBs, although it did not not change cFos levels in either male or female mice. The researchers observed that post-training injections of etoposide led to long-term decreases in both contextual and cued freezing among female mice. Etoposide decreased hippocampal NADPH in females and hippocampal DSBs in both sexes. Overall, etoposide decreased hippocampal γH2Ax (a DSB repair marker), hippocampal NADPH and cortical cFos in a sex-dependent manner.

“Post-training injections of amifostine affected long-term contextual fear memory; etoposide affected contextual and cued fear memory.”

CONCLUSION

“Our results suggest that amifostine and etoposide have distinct effects on learning and memory dependent on sex and timing of administration.”

The researchers assessed the effects of these DSB-altering agents and found results suggesting that they have a direct impact on learning and memory. Their impacts varied on the basis of sex and timing of administration before or after training. The researchers suggest that future studies examine these effects on specific brain regions to clarify the underlying mechanisms driving learning and memory changes.

“Newer analogs of these drugs, such as PrC-210 [45], might reduce these side effects and improve patients’ quality of life. Future investigations are warranted to determine the role of DSBs in encoding, retrieval, and reconsolidation, and further our understanding of learning and memory processes in health and disease.”

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

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