Tag Archives: #leukemia

Oncotarget: Iron Chelating Properties in Pediatric Acute Myeloid Leukemia (Medicine)

Oncotarget published “Eltrombopag and its iron chelating properties in pediatric acute myeloid leukemia” which reported that the standard treatment for pediatric AML currently consists in a combination of cytarabine and antracycline.

Eltrombopag, a thrombopoietin receptor agonist used in immune thrombocytopenia, shows anticancer properties related to its emerging iron chelating properties.

The authors compare the anticancer effect of classically used cytarabine with DFX and ELT effects in a pediatric AML cell line, THP-1, in order to identify innovative and more effective therapeutic strategies.

ELT and DFX reduce intracellular iron concentration by inhibiting its uptake and by promoting its release.

In particular, even though further investigations are needed to better understand the exact underlying action mechanisms, this Oncotarget Research Output demonstrated that ELT improves cytarabine antineoplastic activity in pediatric AML cell lines.

This Oncotarget Research Output demonstrated that ELT improves cytarabine antineoplastic activity in pediatric AML cell lines.

Dr. Francesca Rossi from The University of Campania Luigi Vanvitelli said, “Acute myeloid leukemia (AML) represents the 20% of total childhood leukemia diagnoses [1], even though it remains the most frequent type of acute leukemia in the elderly.

The altered iron metabolism in AML patients is also strongly related to a dysregulation in the expression of iron metabolism mediators at AML cells level.

European Medicines Agency approved three iron chelators for treatment of iron overload conditions: deferoxamine generally used in thalassemia major, deferiprone and deferasirox instead indicated in leukemic patients.

It was demonstrated that ELT mobilizes iron from the intracellular compartment, thus reducing the metal availability for cancer cell metabolic processes, and proposed a shuttling mechanism when ELT and DFX are combined.

In particular, ELT decreases cellular iron and further enhances iron mobilization, donating it to DFX.

In this Oncotarget study the authors tested cytarabine, the most commonly used anticancer drug in AML, with both DFX, one of the most diffused iron chelators in leukemia, and ELT, an emerging iron chelating agent, in THP-1 cell line.

The Rossi Research Team concluded, “our study lets emerge a promising synergism between ELT and cytarabine with reduction in viability, increase in apoptosis and arrest of both proliferation and cycle progression in the pediatric AML cell line THP-1. On the other hand, we can not confirm the effectiveness of DFX in AML, neither alone neither in combination with the classically used chemotherapy agent. Further investigations are certainly needed to clarify the exact mechanisms underlying the synergism between ELT and cytarabine, in particular to understand whether ELT iron chelating properties are actually responsible for these anticancer activities. However our results encourage the possibility to combine them to increase the outcome of canonic therapeutic strategy in AML, reducing dose-related side effects associated to cytarabine as well as the chemo-resistance often developed by patients against this agent.

DOI – https://doi.org/10.18632/oncotarget.28000

Full text – https://www.oncotarget.com/article/28000/text/

Featured image:  Effect of 48-hour treatments on proliferation. NFkB protein expression level in THP-1 cell line was determined by Western Blot, starting from 15 μg of total lysates after 48 h of exposure to ELT, DFX and Cytarabine, alone and in combination. The most representative cropped images of blots are displayed. The proteins were detected using Image Studio Digit software and the intensity ratios of immunoblots compared to that of untreated control, taken as 1 (arbitrary unit), were quantified after normalizing with respective loading controls for the housekeeping protein β-Actin. The histogram represents the relative quantification for NFkB expression as mean ± SD of three independent experiments A t-test has been used to evaluate the statistical differences in protein expression levels. * indicates p ≤ 0.05 compared to non-treated sample (NT). © Correspondence to – Francesca Rossi – francescarossi@unicampania.it


Reference: Argenziano M., Tortora C., Paola A. Di, Pota E., Martino M. Di, Pinto D. Di, Leva C. Di, Rossi F. Eltrombopag and its iron chelating properties in pediatric acute myeloid leukemia. Oncotarget. 2021; 12: 1377-1387. Retrieved from https://www.oncotarget.com/article/28000/text/


Provided by Impact Journals LLC

Eliminating RNA-binding Protein Improves Survival in Aggressive Leukemia (Medicine)

Removing a protein that is often overexpressed in a rare and aggressive subtype of leukemia can help to slow the cancer’s development and significantly increase the likelihood of survival, according to a study in mice led by scientists at the UCLA Jonsson Comprehensive Cancer Center.

The research, published today in the journal Leukemia, could aid in the development of targeted therapies for cancers that have high levels of the RNA-binding protein IGF2BP3—especially acute lymphoblastic and myeloid leukemias that are characterized by chromosomal rearrangements in the mixed lineage leukemia (MLL) gene.

In these MLL-rearranged leukemias, IGF2BP3 attaches to certain RNA molecules that carry genetic instructions for cancer-related proteins, markedly amplifying cancer development. Children and adults diagnosed with this subtype have a poor prognosis and a high risk of relapse after treatment.

“This type of leukemia is more aggressive because of its ability to divide and spread faster,” said senior author Dr. Dinesh Rao, a member of the Jonsson Cancer Center and an associate professor of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA. “The disease can be very difficult to treat, even with new targeted immunotherapies like CAR T cell therapy and blinatumomab.”

Leukemia begins in the bone marrow and is spurred by genetic mutations that cause stem cells in the marrow to produce too many white blood cells, affecting the body’s ability to fight infection. Rao and his team had earlier identified IGF2BP3 as a factor in driving the development of leukemia—particularly the MLL-rearranged subtype—by regulating various RNA messages that contribute to the disease.

Taking this into account, the researchers wondered whether removing the IGF2BP3 protein might stop the proliferation of leukemia cells. To answer the question, Rao and his team used the powerful gene-editing tool known as CRISPR-Cas9 to remove IGF2BP3 from both MLL-leukemic mice and cell lines. The effects on survival, they found, were striking.

Of the leukemic mice that had IGF2BP3 deleted, approximately 75% had an increase in overall survival, and 50% were leukemia-free. The team also observed an average fourfold reduction in the mice’s tumor burden—the total mass of tumor tissue in the body—after IGF2BP3 removal, as measured by the weight of their spleens.

“These results really highlight IGF2BP3 as an attractive and valuable therapeutic target,” said lead author Tiffany Tran, a graduate student researcher in UCLA’s molecular, cellular and integrative physiology interdepartmental doctoral program. “By targeting this RNA-binding protein, we would be able to target the cancer cells directly and leave the healthy, non-cancerous cells alone.”

In targeting IGF2BP3, the team also discovered that the protein was not necessary for normal blood development in mice; the blood system appeared mostly intact when the protein was removed. Even mice that were completely deficient of the protein developed normally.

“This was surprising to us because a lot of proteins that are important in cancer are also important in normal tissues,” said Rao, who is also a member of the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research.

“This is also an attractive target because we have made some real advances in understanding how it works in the cancer cells,” Rao added. “We were able to pinpoint some important RNA molecules that it binds to, which encode other cancer-causing proteins. So if you can remove this protein, you’re able to modify the amount of other cancer-causing proteins.”

While the team studied IGF2BP3 as a target in MLL leukemias, the protein is also highly expressed in about 15% to 20% of other cancer types, including glioblastoma, pancreatic cancer, lung cancer and melanoma.

The next step for researchers is to understand whether the removal of the protein has as strong of an effect against other types of cancer, as well as to develop small-molecule and RNA-based therapeutics to try to interfere with the function of the protein.

Featured image: Acute lymphoblastic leukemia, bone marrow smear, 3D illustration – Image Credit: Kateryna Kon / Shutterstock


Reference: Tiffany M. Tran et al, The RNA-binding protein IGF2BP3 is critical for MLL-AF4-mediated leukemogenesis, Leukemia (2021). DOI: 10.1038/s41375-021-01346-7


Provided by University of California, Los Angeles

Pulse Therapy With Vincristine and Dexamethasone For Childhood Leukemia (Medicine)

Scientists at St. Jude Children’s Research Hospital are working with colleagues in China to develop better therapy for childhood acute lymphoblastic leukemia (ALL). Results from a large phase 3 noninferiority clinical trial definitively showed that vincristine and dexamethasone pulses can be eliminated in patients with low-risk disease. The findings were published today in The Lancet Oncology.

Adding the chemotherapy vincristine plus a steroid (originally prednisone, and later dexamethasone) as pulse therapy for childhood ALL has been part of standard care since the 1970s. This is despite their being associated with neuropsychological side effects, neuropathy and other late effects. However, to date studies about the need for prolonged treatment with pulse therapy have been inconclusive.

“We wanted to study this issue to provide definitive conclusions about whether we can safely omit prolonged pulse therapy with these two drugs to improve quality of life for patients and lessen the burden to their family,” said corresponding author Ching-Hon Pui, M.D., St. Jude Department of Oncology chair. “That’s why doing this study through the Chinese Children’s Cancer Group was key: a definitive noninferiority randomized trial of a disease with a high cure rate such as ALL requires very large numbers of patients all treated consistently.”

Clinical trial provides clarity

Between January 2015 and February 2019, children with newly diagnosed ALL joined a randomized, open-label, phase 3 noninferiority study as part of the Chinese Children’s Cancer Group ALL-2015 protocol. This clinical trial randomized 6,108 patients, making it the largest clinical trial ever conducted in childhood acute lymphoblastic leukemia.

Patients in continuous remission for one year were stratified and randomized to receive or not receive seven pulses of vincristine plus dexamethasone during the second year of treatment. Using the noninferiority study design, researchers firmly established that pulse therapy can be safely omitted in the second year of care in patients with low-risk disease without affecting their five-year event-free survival or overall survival.

Omitting vincristine plus dexamethasone pulses after the first year of treatment in these children should reduce many acute and late effects of treatment as well as the burden on their families. Additional studies are needed to confirm whether this is true for patients with intermediate or high-risk ALL.

“These findings are very good news for patients and families because shortening this pulse therapy will substantially reduce neuropsychological side effects, emotional disturbances and many other neurological and metabolic late effects,” Pui said.

Featured image: FatCamera/Getty Images


Reference: Wenyu Yang et al, Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial, The Lancet Oncology (2021). DOI: 10.1016/S1470-2045(21)00328-4


Provided by St. Jude Children’s Research Hospital

Ibrutinib Effective Treatment For Difficult To Treat Forms of Hairy Cell Leukemia (Medicine)

The oral targeted therapy drug ibrutinib is an effective treatment option for high-risk hairy cell leukemia, according to a new study conducted by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

Hairy cell leukemia is a rare form of B-cell blood cancer that is diagnosed in 600 to 800 people annually in the United States. Researchers note that while the disease generally has a good prognosis for the majority of people affected, a small group of patients with variants of the disease do not respond well to existing U.S. Food and Drug Administration (FDA) approved therapies or cannot tolerate the side effects of established therapies.

“There is a critical unmet need for therapy options in this subset of patients to achieve long-term cancer control,” said Kerry Rogers, MD, principal investigator of the clinical trial and a hematologist/scientist at the OSUCCC – James. “Our study shows that ibrutinib (pronounced eye-broo-ti-nib) is a safe, effective and well-tolerated option for patients with relapsed or variant forms of hairy cell leukemia. It is a very important discovery for patients facing this diagnosis.”

For this phase 2 clinical trial, a multi-institutional team led by the OSUCCC – James recruited 44 patients with high-risk hairy cell leukemia to test the effectiveness of the drug ibrutinib, 15 of whom were treated in Columbus, Ohio, at the OSUCCC – James.

All study participants had either classic hairy cell leukemia and had received other treatments previously or the variant form of the disease where it is not likely that the standard therapies — the chemotherapy drugs cladribine (pronounced KLAD-rih-been) and pentostatin (pronounced PEN-toh-STA-tin) — would be effective.

Researchers reported their findings in the June 24 issue of Blood.

Ibrutinib is an oral therapy in a class of drugs known as Bruton’s tyrosine kinase (BTK) inhibitors. These drugs block specific chemical reactions in the body that are involved in cellular processes. Use of the drug for this study was considered experimental; however, ibrutinib is FDA approved for the treatment of certain cancers, including mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma and others.

“The underlying cellular biology of these diseases is similar, so we wanted to determine if this FDA-approved drug that is used to treat other forms of blood cancer could also serve as an effective treatment for this small segment of hairy cell leukemia patients who did not respond to traditional therapies,” said Rogers, who is an assistant professor in Ohio State’s College of Medicine.

“Even though hairy cell leukemia is a disease with a generally good prognosis, there is a small group of patients for whom current therapies are inadequate for cancer control,” Rogers added. “This is an effective, well-tolerated new treatment option for patients impacted by the highest-risk forms of hairy cell leukemia. It’s a very exciting development that could transform survivorship for this subset of patients from months and years, to years and decades.”

This study was sponsored by the Cancer Therapy Evaluation Program at the National Cancer Institute and grants from the National Cancer Institute/National Institutes of Health and conducted at the OSUCCC – James; the NCI clinical trials center, Karmanos; Mayo Clinic and MD Anderson Cancer Center. The study began in 2013 and is closed to patient accrual.

Featured image: Hairy cell leukemia slide © OSU


Reference: Kerry A. Rogers, Leslie A. Andritsos, Lai Wei, Eric M. McLaughlin, Amy S. Ruppert, Mirela Anghelina, James S. Blachly, Timothy Call, Dai Chihara, Anees Dauki, Ling Guo, S. Percy Ivy, Lacey R. James, Daniel Jones, Robert J. Kreitman, Gerard Lozanski, David M. Lucas, Apollinaire Ngankeu, Mitch Phelps, Farhad Ravandi, Charles A. Schiffer, William E. Carson, Jeffrey A. Jones, Michael R. Grever; Phase 2 study of ibrutinib in classic and variant hairy cell leukemia. Blood 2021; 137 (25): 3473–3483. doi: https://doi.org/10.1182/blood.2020009688


Provided by OSU

Ficlatuzumab Plus Chemotherapy May Benefit Patients With Relapsed/Refractory AML (Medicine)

Bottom Line: The investigational therapeutic ficlatuzumab in combination with chemotherapy showed signs of clinical efficacy in patients with relapsed/refractory acute myeloid leukemia.

Journal in Which the Study was Published: Blood Cancer Discovery, a journal of the American Association for Cancer Research

Author: Senior author Charalambos Andreadis, MD, professor of clinical medicine at the University of California, San Francisco (UCSF), and first author Victoria Wang, MD, PhD, an assistant professor of hematology and oncology at UCSF

Background: “Only about half of patients with acute myeloid leukemia (AML) will achieve long-term disease control,” said Andreadis. Patients whose AML relapses or does not respond to initial therapy have worse outcomes, Andreadis explained. These patients typically undergo subsequent multi-agent chemotherapy, a toxic treatment with limited success in this population, he added.

“Unfortunately, patients whose cancers relapse or don’t respond to initial therapy face a poor outlook, as only 30 to 40 percent of these patients respond to subsequent multi-agent chemotherapy and even fewer develop long-term remissions. Most patients will eventually succumb to their disease,” he said.

New therapies targeting AML-specific mutations have been developed in recent years; however, these target select patients, highlighting the need for new, widely applicable therapies, according to Andreadis.

How the Study was Conducted: In their study, Andreadis and colleagues evaluated the safety and efficacy of an investigational agent targeting a shared chemical pathway in combination with single-agent chemotherapy in patients with relapsed/refractory AML. The investigational therapy, ficlatuzumab, is a first-in-class monoclonal antibody that binds the extracellular hepatocyte growth factor (HGF) to prevent it from activating MET signaling and stimulating tumor growth. “Unlike most existing targeted cancer therapies, ficlatuzumab targets an extracellular factor instead of a cancer-specific mutation,” Andreadis noted, adding that some patients with refractory AML have higher levels of circulating HGF.

The phase I clinical trial enrolled 17 adult patients with AML that was either refractory to prior treatment or that had relapsed within 12 months of prior treatment. Patients received four doses of ficlatuzumab, administered 14 days apart, along with the chemotherapeutic cytarabine.

Results: Nine of 17 patients (53 percent) had a complete response, and four of the responding patients had no signs of minimal residual disease. Among responding patients, the progression-free survival was 31.2 months, and the overall survival was not reached. Ten patients (eight responders and two non-responders) proceeded to allogeneic hematopoietic cell transplantation; six of these patients remained in remission at the most recent follow-up.

The most common adverse event was febrile neutropenia. Serious adverse events occurred in two patients, and there was one death unrelated to the investigational therapy.

To identify molecular changes associated with treatment response, Andreadis and colleagues analyzed peripheral blood mononuclear cells collected at baseline and at several timepoints after treatment initiation. They found that ficlatuzumab treatment led to attenuated phosphorylation of MET, the receptor for HGF, thereby confirming on-target inhibition of HGF. Clinical response to ficlatuzumab treatment was associated with reduced phosphorylation of the S6 protein and increased expression of genes involved in myeloid and leukocyte activation, whereas non-responding patients were more likely to have increased expression of HGF, increased phosphorylation of S6, and expression of genes involved in protein translation, cell adhesion, and type I interferon signaling.

Author’s Comments: “The 53 percent response rate was quite striking to us since historical response rates for the standard-of-care treatment are in the 30 percent range,” noted Andreadis. “While these results need to be validated in a larger study, they suggest that ficlatuzumab in combination with single-agent chemotherapy may lead to better responses with less toxicity in patients with relapsed/refractory AML.”

“By comparing pre-treatment to post-treatment blood samples using state-of-the art single-cell mass cytometry and RNA sequencing, we observed that ficlatuzumab successfully suppressed HGF signaling, and we also identified biomarkers of treatment response and resistance,” said Wang. “This approach provided novel insight into the molecular changes that occur upon treatment, which could have clinical implications for tracking treatment response or identifying patients likely to respond.”

“Together, our findings suggest that targeting an extracellular factor in conjunction with existing cancer therapies could be an effective therapeutic strategy for AML treatment,” said Andreadis.

Study Limitations: Limitations of the study include the small sample size and its single-arm design. Andreadis and Wang noted that since the study was designed to assess safety and dosing, rather than efficacy, additional studies to validate the efficacy findings will be needed. A phase II clinical trial to evaluate ficlatuzumab plus chemotherapy has been initiated. An additional limitation was the lack of bone marrow specimens for the gene expression analyses.

Funding & Disclosures: The study was supported by the National Cancer Institute, the Damon Runyon Postdoctoral Award, the American Society for Clinical Oncology Young Investigator Award, the Department of Defense, and a Gateway for Cancer Grant. Andreadis and Wang declare no conflicts of interest.


Reference: Victoria E. Wang, Bradley W. Blaser, Ravi K. Patel, Gregory K. Behbehani, Arjun A. Rao, Blythe Durbin-Johnson, Tommy Jiang, Aaron C. Logan, Matthew Settles, Gabriel N. Mannis, Rebecca Olin, Lloyd E. Damon, Thomas G. Martin, Peter H. Sayre, Karin M. Gaensler, Emma McMahon, Michael Flanders, Vivian Weinberg, Chun J. Ye, David P. Carbone, Pamela N. Munster, Gabriela K. Fragiadakis, Frank McCormick and Charalambos Andreadis, “Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis”, Cancer Discovery, 2021. DOI: 10.1158/2643-3230.BCD-21-0055


Provided by AACR

Immune Microenvironment As A Driver of Disease Progression in Chronic Lymphocytic Leukemia (Medicine)

  • Research led by VHIO investigators represents a step forward in better understanding the underlying mechanisms that drive disease progression in chronic lymphocytic leukemia (CLL).
  • Results published open-access in Biomarker Research indicate that genetic evolution is not the main driver of CLL progression. Pointing to the involvement of the leukemic immune microenvironment as a co-culprit, these findings shed light on why some patients progress and others do not.
  • Increased immune cell exhaustion was observed in patients with progression. The study of malignant cells in this population showed a greater capacity to escape the immune system.
  • These findings could support the design of clinical studies assessing immunotherapy in early stages of disease to prevent or delay clinical progression, as well as identify novel biomarkers to improve early detection of patients whose disease will likely progress.

Chronic lymphocytic leukemia (CLL) is the most common blood cancer in adults. According to a recent, global study (1) the incidence rates of CLL significantly increased between 1990-2017 in most countries, suggesting that this type of leukemia might become a major global public health concern.

CLL has a highly variable disease course across patients. Almost half present with progressive disease requiring various lines of therapy. The other half have a more indolent disease, needing little or no treatment, and have a longer survival.  While the therapeutic landscape for progressive disease has improved over recent years with the approval of more potent targeted agents, the majority of these patients inevitably experience disease recurrence or persistence.

While important insights have provided a deeper understanding of the underlying biology of this disease, the mechanisms driving the progression of CLL from its early stages are not yet fully understood. Research directed by Francesc Bosch, Principal Investigator of VHIO’s Experimental Hematology Group, sought to identify new biological features of clinical progression by studying the specific changes that occur in patients that progress compared to those occurring in patients who remain asymptomatic along time. Results from this study, recently published as an open access article in Biomarker Research (2), suggest that changes in the immune system could explain why some patients progress and others do not.

Francesc Bosch © VHIO

Findings reported by Francesc Bosch’s group from initial longitudinal genetic studies, carried out at the time of diagnosis and at disease progression before treatment, showed non-recurrent and limited changes in around half of these patients.  This observation led his team to hypothesize that CLL progression is not principally driven by dynamic genetic clonal evolution. “This study is the first comprehensive longitudinal analysis of the genetic and immunological processes driving disease progression in CLL. It has enabled us to establish that genetic changes are not the main drivers of disease progression. Our findings indicate that alterations in the immune microenvironment are highly significant”, commented Marta Crespo, Translational Research Coordinator of VHIO’s Experimental Hematology Group, Vall d’Hebron Barcelona Hospital Campus, and co-corresponding author of the study.

The VHIO investigators analyzed samples at diagnosis and at long-term follow-up of patients with clinical progression, within three to four years between the two, and from patients with stable disease. “We studied the changes that occurred from diagnosis to clinical progression, that were not associated with the subsequent passing of time but differed among patients with progressive CLL compared with those with stable disease”,  added Marta Crespo.

In concordance with previous studies, this longitudinal analysis showed that genetic alterations do not explain disease progression since they occurred randomly, and in both groups of patients. “By investigating the immune system we are starting to reveal differences that could be key to explaining why this disease progresses in some patients and not in others. Changes in immune cells reduce their capacity to recognize and kill malignant cells, and alterations in cancer cells empower them to escape the immune surveillance of tumors”, said Francesc Bosch, co-corresponding author and Head of the Hematology Service at the Vall d’Hebron University Hospital (HUVH).

Altogether, these results could provide a rationale for the use of early immunotherapeutic interventions in early stages of CLL aimed at avoiding or delaying disease progression.  In this respect, their analysis of the immunological changes showed that patients suffering from progressive disease had a greater accumulation of CD8+ T cells showing increased, terminal exhaustion. This increased exhaustion can be induced by interleukin- 10 secreted by leukemic cells. In patients with progression the VHIO investigators also observed an increase in the expression of some inhibitory receptors of the immune system such as PD1, CD244 or CD160All these changes lead to a more rapid deterioration of the immune system; reducing its capacity to hone in on and attack malignant cells.

“Additional analysis of both immunological and malignant cell-intrinsic factors in larger cohorts of patients will help us to better identify those patients who are more likely to progress shortly after diagnosis, and more precisely guide clinical decision-making”, concluded Marta Crespo.

Featured image: Dr. Marta Crespo © VHIO


References

  1. Dong Y, Shi O, Zeng Q, Lu X, Wang W, Li Y, Wang Q. Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol. 2020 Jun 19;9:14.
  2. Jiménez I, Tazón-Vega B, Abrisqueta P, Nieto JC, Bobillo S, Palacio-García C, Carabia J, Valdés-Mas R, Munuera M, Puigdefàbregas L, Parra G, Esteve-Codina A, Franco-Jarava C, Iacoboni G, Terol MJ, García-Marco JA, Crespo M, Bosch F. Immunological and genetic kinetics from diagnosis to clinical progression in chronic lymphocytic leukemia. Biomark Res. 2021 May 20;9(1):37.

Provided by VHIO

Oncotarget: Inhibitory Effects Of Tomivosertib in Acute Myeloid Leukemia (Medicine)

Oncotarget published “Inhibitory effects of Tomivosertib in acute myeloid leukemia” which reported that the authors evaluated the therapeutic potential of the highly-selective MNK1/2 inhibitor Tomivosertib on AML cells.

Tomivosertib was highly effective at blocking eIF4E phosphorylation on serine 209 in AML cells.

Moreover, combination of Tomivosertib and Venetoclax resulted in synergistic anti-leukemic responses in AML cell lines.

Mass spectrometry studies identified novel putative MNK1/2 interactors, while in parallel studies we demonstrated that MNK2 – RAPTOR – mTOR complexes are not disrupted by Tomivosertib.

Overall, these Oncotarget findings demonstrate that Tomivosertib exhibits potent anti-leukemic properties on AML cells and support the development of clinical translational efforts involving the use of this drug, alone or in combination with other therapies for the treatment of AML.

These Oncotarget findings demonstrate that Tomivosertib exhibits potent anti-leukemic properties on AML cells and support the development of clinical translational efforts involving the use of this drug

Dr. Leonidas C. Platanias from The Northwestern University as well as The Jesse Brown Veterans Affairs Medical Center said, “Acute myeloid leukemia (AML) is the second most common form of leukemia in adults, and has a very poor overall survival rate.

Therefore, there continues to be a need for new therapeutic modalities, including approaches targeting negative-feedback signaling pathways that may be activated in response to antileukemic treatments, leading to resistance.

The pro-neoplastic activity of eIF4E is associated with its phosphorylation/activation by MNK1/2 on serine 209 and correlates with enhanced mRNA translation, as well as nuclear export of mRNAs involved in tumorigenesis and cell cycle control.

Several studies have shown that pharmacological targeting of MNK1/2 results in inhibitory activity against AML cells in pre-clinical models.

As a result, the full therapeutic potential of MNK1/2 inhibition for the treatment of AML has not been fully assessed.

The authors demonstrate that Tomivosertib suppresses eIF4E phosphorylation in AML cells and decreases leukemic cell survival and proliferation.

The Platanias Research Team concluded in their Oncotarget Research Output, “Viewed altogether, these studies indicate that MNK1/2 inhibition would most likely be a successful strategy in only a subset of AML patients. In future studies it will be crucial to ascertain what pathways are responsible for sensitivity to MNK inhibitors. These studies will help to identify potential regulatory programs through which MNK1/2 modulates cell signaling pathways critical for leukemic cell survival and may lead to the development of novel therapeutic interventions for AML.

DOI – https://doi.org/10.18632/oncotarget.27952

Full text – https://www.oncotarget.com/article/27952/text/

Featured image: LC-MS/MS analysis identifies putative MNK1/2 targets and interactors. (A) FLAG-MNK2 or FLAG-MNK1 was overexpressed in 293T cells. MNK1/2 was immunoprecipitated from 293T cell lysates using anti-FLAG-M2 agarose conjugated beads. An empty vector was used as a negative control. Immunoprecipitated proteins were resolved by SDS-PAGE, and were prepared using standard techniques and then analyzed via LC-MS/MS. A Venn diagram was created depicting the number of proteins that interact with MNK1/2. (B) The results from (A) were annotated using Metascape. The heat map shows the most significant pathways and the overlap between the MNK1 IP and MNK2 IP. (C) FLAG-MNK2 or FLAG-MNK1 was immunoprecipitated as described in (A). Proteins were resolved by SDS-PAGE and immunoblotted with the indicated antibodies. (D) FLAG-MNK2 was overexpressed in 293T cells. Cells were treated with either DMSO (vehicle-control) or Tomivosertib at the indicated doses and time points, lysed and MNK2 was immunoprecipitated with anti-FLAG-M2 agarose conjugated beads. An empty vector (EV) was used as a negative control. Proteins were resolved by SDS-PAGE and immunoblotted with the indicated antibodies. (E) HA-RAPTOR was overexpressed in 293T cells. Cells were treated with either DMSO (vehicle-control) or Tomivosertib at the indicated doses and time points, lysed and RAPTOR was immunoprecipitated with anti-HA Sepharose conjugated beads. An empty vector (EV) was used as negative control. Proteins were resolved by SDS-PAGE and immunoblotted with the indicated antibodies. (C–E) Total cell lysates for each experimental condition were run in parallel with the immunoprecipitated proteins (Input). © Milagros Suarez et al.


Reference: Suarez M., Blyth G. T., Mina A. A., Kosciuczuk E. M., Dolniak B., Dinner S., Altman J. K., Eklund E. A., Saleiro D., Beauchamp E. M., Platanias L. C. Inhibitory effects of Tomivosertib in acute myeloid leukemia. Oncotarget. 2021; 12: 955-966. Retrieved from https://www.oncotarget.com/article/27952/text/


Provided by Impact Journals LLC

Can Leukemia in Children With Down Syndrome be Prevented? (Medicine)

Princess Margaret Scientists reveal a new target that suggests it can

For the first time, Princess Margaret researchers have mapped out where and how leukemia begins and develops in infants with Down syndrome in preclinical models, paving the way to potentially prevent this cancer in the future.

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia within the first five years of their life. Yet the mechanism by which the extra copy of chromosome 21 predisposes to leukemia remains unclear.

Down syndrome is a genetic disorder caused by a random error in cell division in early human development that results in an extra copy of chromosome 21. This extra copy is what causes the developmental changes and physical traits associated with the syndrome, including the predisposition to leukemia.

However, the exact blood cell type in which leukemia begins in fetal development, along with the genetic alterations that cause this cell to become preleukemic, has eluded researchers until now. Furthermore, the additional mutations that must accumulate during childhood to transform preleukemia into acute leukemia were unknown.

The study and results of the early evolution of leukemia in Down syndrome from the laboratory of Princess Margaret Senior Scientist Dr. John Dick are published in Science, July 9, 2021. Post-doctoral fellow Dr. Elvin Wagenblast is first author, and Affiliate Scientist Dr. Eric Lechman is co-senior author, along with Dr. Dick.

Dr. Eric Lechman, Affiliate Scientist at the Princess Margaret Cancer Centre, University Health Network, is co-senior author. © UHN

“A whole sequence of cellular events have already happened before a person is diagnosed with the disease,” explains Dr. Dick. “You can’t tell at that point which sequence of events happened first, you just know that it has already happened.

“For the first time, our model is giving us insight into the human leukemia process. Ultimately, we may be able to prevent the acute illness by treating it in its earliest phase, when it is preleukemic, to prevent its progression to full blown leukemia.”

Using a preclinical model that includes human Down syndrome cells from a human tissue biobank, along with an enhanced CRISPR/Cas9 method for gene alteration in human blood stem cells that was developed by Drs. Wagenblast and Lechman at Princess Margaret, the team set out to chart the steps involved in this specific leukemia evolution.

Transient preleukemia is a unique condition frequently occurring in newborns with Down syndrome, which can either spontaneously disappear within days to months of birth, or transform into acute myeloid leukemia within four years by acquiring additional mutations in some individuals.

What Drs. Wagenblast, Lechman and Dick revealed in this work was the distinct cellular and genetic events related to transient preleukemia, from their beginnings in the fetus, to further progression to leukemia in childhood.

Dr. John Dick, Senior Scientist at the Princess Margaret Cancer Centre, University Health Network, is co-senior author. © UHN

Specifically, the team was able to test a variety of blood cell types and pinpoint that transient preleukemia originates only from long-term hematopoietic stem cells (HSCs), with the GATA1 mutation, as early as the second trimester of a fetus with Down syndrome. Preleukemia does not begin in HSCs from non-Down syndrome samples.

Only HSCs are able to regenerate the entire blood system and maintain long-term output due to their unique continuous capacity for self-renewal. In a broader picture, the fact that the cellular origin of pediatric leukemia is limited to only long-term HSCs might have implications for other kinds of childhood leukemias beyond Down syndrome.

Acute leukemia happens only after the first two mutations – the extra copy of chromosome 21 and the GATA1 mutation – are in place and have “primed” the progeny or descendants downstream of the altered long-term HSCs to acquire further mutations that lead to fully transformed acute leukemia, explains Dr. Lechman.

“We actually created a human disease in a preclinical model by showing how the genetically edited, as well as the normal human blood stem cells, behave in it, and we succeeded in recreating the precise, progressive steps of how leukemia develops,” says Dr. Dick. “We now have a lot of clues as to the genetic abnormalities these mutations are driving when they cause leukemia.”

The team also identified CD117/KIT as a unique protein cell surface marker on the altered disease-driving stem cells that causes the cells to proliferate. In the preclinical model and setting, the researchers were able to target and eliminate preleukemic stem cells using small molecule CD117/KIT inhibitors to prevent their progression to acute leukemia.

The researchers note that this preventative strategy could potentially be used in Down syndrome newborns and even expanded to other childhood leukemias that are known to be initiated during fetal development.

“The clinical significance of being able to target pre-cancerous lesions and preventing progression to cancer is profound,” says Dr. Dick, “It would transform the pediatric cancer field.”

The work was supported by the Human Frontier Science Program, Alex’s Lemonade Stand Foundation, The Leukemia & Lymphoma Society and The Leukemia & Lymphoma Society of Canada, Portuguese Foundation for Science and Technology, Princess Margaret Cancer Centre Foundation, Ontario Institute for Cancer Research, Canadian Institutes for Health Research, International Development Research Centre, Canadian Cancer Society, Terry Fox Research Institute Program Project Grant, University of Toronto’s Medicine by Design.

Featured image: Dr. Elvin Wagenblast, Post-doctoral Fellow at the Princess Margaret Cancer Centre, University Health Network, is the first author. © UHN


Reference: Elvin Wagenblast, Joana Araújo, Olga I. Gan, Sarah K. Cutting, Alex Murison, Gabriela Krivdova, Maria Azkanaz, Jessica L. McLeod, Sabrina A. Smith, Blaise A. Gratton, Sajid A. Marhon, Martino Gabra, Jessie J. F. Medeiros, Sanaz Manteghi, Jian Chen, Michelle Chan-Seng-Yue, Laura Garcia-Prat, Leonardo Salmena, Daniel D. De Carvalho, Sagi Abelson, Mohamed Abdelhaleem, Karen Chong, Maian Roifman, Patrick Shannon, Jean C. Y. Wang, Johann K. Hitzler, David Chitayat, John E. Dick, Eric R. Lechman, “Mapping the cellular origin and early evolution of leukemia in Down syndrome”, Science  09 Jul 2021: Vol. 373, Issue 6551, eabf6202 DOI: https://doi.org/10.1126/science.abf6202


Provided by University Health Network

Combination Targeted Therapy Provides Durable Remission for patients with Chronic Lymphocytic Leukemia (Medicine)

Oral targeted therapy achieved three-year overall survival rate of 96%

A combination of ibrutinib and venetoclax was found to provide lasting disease remission in patients with newly diagnosed chronic lymphocytic leukemia (CLL), according to researchers at The University of Texas MD Anderson Cancer Center. Findings from the single-institution Phase II study were published today in JAMA Oncology and provide the longest follow-up data on patients treated with this drug regimen.

Lead researchers included Nitin Jain, M.D., associate professor of LeukemiaWilliam Wierda, M.D., Ph.D., professor of Leukemia; and Varsha Gandhi, Ph.D., department chair ad interim of Experimental Therapeutics.

MD Anderson researchers previously reported results from this study showing that ibrutinib and venetoclax were effective when given together for high-risk and older patients with the disease. This report offers an additional two years of follow-up data and statistics on bone marrow undetectable measurable residual disease (U-MRD) after treatment. Overall, the three-year progression-free survival was 93% and the three-year overall survival was 96%. The response rates were the same for the high-risk subgroup of patients.

“CLL is the most common leukemia in the United States and was originally treated with chemoimmunotherapy,” said Jain. “These long-term results show that two years of oral targeted therapy can achieve lasting disease remission for patients with CLL.”  

Researchers followed 80 previously untreated patients with a median age of 65 years, 30% of whom were over age 70. Overall, 92% had high-risk genetic anomalies. The median follow-up for all 80 patients was 38.5 months. Trial participants were 94% white, 4% other, 1% American Indian or Alaska Native and 1% unknown.

The U-MRD responses improved with ongoing combined ibrutinib plus venetoclax. After 12 cycles of combination therapy, 56% of patients achieved bone marrow U-MRD, and after 24 cycles of combination therapy, 66% of patients achieved bone marrow U-MRD remission. A total of 75% of patients achieved bone marrow U-MRD remission at any time during the study.

“MRD is one of the most important prognostic markers at the end of leukemia treatment,” said Jain. “The majority of patients achieved bone marrow MRD remission and no patients on the trial had CLL disease progression.”

The research team continues to monitor the patients’ MRD every six months and is working on further correlative studies. The treatment was well-tolerated and the toxicity profile of both drugs was consistent with other studies, with no additional toxicity observed with the combination.

Several ongoing studies are investigating combined BTK inhibitors with venetoclax, including the CAPTIVATE trial, which reported results at the recent American Society of Clinical Oncology (ASCO) annual meeting, the UK FLAIR trial, the CLL17 trial, and the CLL GLOW trial, which will report Phase III results at European Hematology Association (EHA) Virtual Congress. Data from these trials and others will clarify the duration and role of this treatment regimen.

“I think this will be one of several standard of care treatments available for patients with CLL,” Jain said. “There are pros and cons to each of those approaches, and physicians will have to decide which option is best for their patient.”

The trial was supported by the Chronic Lymphocytic Leukemia (CLL) Moon Shot®, part of MD Anderson’s Moon Shots Program®, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

Additional research support was provided by AbbVie, the Andrew Sabin Family Foundation, the CLL Global Research Foundation and the National Cancer Institute (P30CA016672).

A full list of co-authors and author disclosures can be found in the paper.


Provided by MD Anderson Cancer Center