Tagged: acute myeloid leukemia

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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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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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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Trending With Impact: New Pre-Transplant AML Treatment Combinations

February 17, 2022

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 from the 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 and exposed 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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