Tagged: Leukemia

Combating Doxorubicin-Resistant Acute Myeloid Leukemia

May 23, 2024

In this new study, researchers examined the impact of MIA-602 as monotherapy and in combination with Doxorubicin on three Doxorubicin-resistant acute myeloid leukemia cell lines.

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Upon diagnosing acute myeloid leukemia (AML), the initial step involves assessing a patient’s eligibility for intensive chemotherapy. The standard treatment protocol for newly diagnosed AML encompasses intensive chemotherapy to achieve complete remission, followed by post-remission therapy, which may include additional chemotherapy and/or stem cell transplantation. Complete response rates to this approach range from 60% to 85% in adults aged 60 or younger.

While this approach has proven effective, the risk of relapse within three years of diagnosis remains a significant concern. Numerous factors contribute to the likelihood of relapse, including short duration of remission, genetic derangements, prior allogeneic transplantation, advanced age, and concomitant comorbidities. These negative prognostic factors underscore the need for continuous exploration of novel therapeutic agents, as relapse remains a formidable barrier to treatment success.

In a new study, researchers Simonetta I. Gaumond, Rama Abdin, Joel Costoya, Andrew V. Schally (awarded the Nobel Prize in Physiology or Medicine in 1977), and Joaquin J. Jimenez from the University of Miami, Florida Atlantic University and Veterans Affairs Medical Center, Miami, investigated newly emerging therapies targeting drug resistance in AML. On April 8, 2024, their new research paper was published in Oncotarget’s Volume 15, entitled, “Exploring the role of GHRH antagonist MIA-602 in overcoming Doxorubicin-resistance in acute myeloid leukemia.”

Drug Resistance: A Persistent Obstacle

Drug resistance poses a substantial challenge in the treatment of AML, often hindering successful outcomes. This resistance can manifest in two distinct forms:

Primary Drug Resistance: Inherent resistance to specific therapeutic agents, present from the outset of treatment.
Acquired Drug Resistance: Resistance developed over the course of treatment, potentially due to various underlying mechanisms.

These resistance pathways involve intricate interplay between drug resistance-related proteins, enzymes, genes, microRNAs, and aberrant signaling pathways, highlighting the complexity of this phenomenon.

Exploring the Potential of GHRH Antagonists in AML Treatment

Growth hormone-releasing hormone (GHRH) is a neuropeptide hormone primarily released by the hypothalamus, canonically known for its role in inducing the release of growth hormone from the pituitary gland. However, GHRH’s influence extends beyond this endocrine axis, acting as a growth factor in various cancer types and normal tissues through an autocrine/paracrine mechanism.

Previous studies have demonstrated the expression of GHRH receptors (GHRH-R) in human AML cell lines, including K-562, THP-1, and KG-1A. Notably, the GHRH antagonist MIA-602 has exhibited the ability to inhibit the proliferation of these leukemic cells both in vitro and in preclinical mouse models.

MIA-602, a synthetic GHRH antagonist, has garnered significant attention for its potential in circumventing drug resistance and mitigating the adverse effects associated with conventional chemotherapy. Numerous studies have documented the anti-oncogenic mechanisms of GHRH antagonists, which encompass:

-Downregulation of NF-κB and beta-catenin

-Upregulation of caveolin-1 and E-cadherin

-Activation of pro-apoptotic pathways

-Modulation of inflammatory cytokines

-Inhibition of the Akt signaling pathway

These diverse mechanisms underscore the multifaceted approach through which MIA-602 exerts its anti-cancer effects, targeting various aspects of oncogenesis, including cellular proliferation, survival, and motility. Importantly, GHRH antagonists have been implicated in the in vitro inhibition of a wide range of cancer cell lines, spanning from acute promyelocytic leukemia (APL) and AML to estrogen-independent breast cancer, clear cell ovarian cancer, glioblastoma, gastric cancer, prostate cancer, and endometrial adenocarcinoma.

Investigating the Impact of MIA-602 on Doxorubicin-Resistant AML Cell Lines

In Vitro Evaluation: Unveiling Promising Results

In the current study, Gaumond et al. evaluated the impact of MIA-602 as a monotherapy and in combination with the chemotherapeutic agent Doxorubicin on three Doxorubicin-resistant AML cell lines: KG-1A, U-937, and K-562. The in vitro results revealed a remarkable reduction in cell viability across all treated wild-type cells, underscoring the efficacy of MIA-602.

Notably, the Doxorubicin-resistant clones exhibited a comparable susceptibility to MIA-602 as their wild-type counterparts. This finding suggests that MIA-602’s mechanism of action is distinct from that of Doxorubicin, enabling it to circumvent the resistance pathways that render Doxorubicin ineffective.

When treated with MIA-602 alone, the following decreases in cell viability were observed:

-KG-1A: 53.5% (wild-type) and 54.5% (Doxorubicin-resistant)

-U-937: 49% (wild-type) and 51.25% (Doxorubicin-resistant)

-K-562: 79.25% (both wild-type and Doxorubicin-resistant)

These results highlight the potent anti-proliferative effects of MIA-602 on AML cell lines, irrespective of their Doxorubicin resistance status. Furthermore, the combination treatment of Doxorubicin and MIA-602 yielded even more remarkable outcomes:

-KG-1A: 80.25% decrease in wild-type cell viability and 57.5% reduction in Doxorubicin-resistant cells

-U-937: 92.5% decrease in wild-type cells and 52.75% reduction in Doxorubicin-resistant cells

-K-562: 88.75% reduction in wild-type cell viability and 78.25% decrease in Doxorubicin-resistant cells

These findings suggest a potential synergistic effect between MIA-602 and Doxorubicin, highlighting the therapeutic potential of this combination approach in overcoming drug resistance.

In Vivo Validation: Corroborating the Therapeutic Efficacy

To further substantiate the in vitro observations, an in vivo experiment was conducted using nude mice xenografted with Doxorubicin-resistant K-562 cells. The mice were randomly divided into two groups: one receiving a control diluent and the other treated with MIA-602 at a dose of 10 μg twice daily for 28 days.

After the treatment period, the control group exhibited a tumor volume of 1114 mm³, while the MIA-602 monotherapy group demonstrated a significantly reduced tumor volume of 629 mm³ – a remarkable decrease of 485 mm³. This finding further reinforces the therapeutic potential of MIA-602 in combating Doxorubicin-resistant AML.

Exploring the Mechanisms of Action and Future Directions

While the anti-oncogenic mechanisms of GHRH antagonists have been extensively studied in various cancer types, further investigation is warranted to elucidate the specific transcriptional effects of GHRH antagonism in Doxorubicin-resistant AML cell lines. Understanding these molecular pathways could pave the way for more targeted and effective therapeutic strategies.

Another area of interest lies in exploring the potential influence of genetic AML subtypes on the response to GHRH antagonist therapy. By examining the expression levels of GHRH receptors across different AML subtypes, researchers can gain insights into the therapeutic potential of MIA-602 and its potential for personalized treatment approaches.

The observed synergistic effects of MIA-602 and Doxorubicin in combating Doxorubicin-resistant AML cell lines warrant further exploration of combination therapies. By strategically combining MIA-602 with other chemotherapeutic agents or targeted therapies, researchers may uncover novel treatment regimens with enhanced efficacy and reduced adverse effects.

Ultimately, the successful translation of these preclinical findings to clinical settings will be crucial in realizing the full potential of MIA-602 as a therapeutic option for Doxorubicin-resistant AML. Well-designed clinical trials will be essential to evaluate the safety, efficacy, and optimal dosing regimens of MIA-602, both as a monotherapy and in combination with other treatments.

Conclusion: Paving the Way for Improved Outcomes

The discovery of MIA-602’s ability to overcome Doxorubicin resistance in acute myeloid leukemia represents a significant step forward in the quest for more effective and targeted therapies. By leveraging the unique mechanisms of action of GHRH antagonists, researchers have unveiled a promising therapeutic approach that circumvents the limitations of conventional chemotherapy.

While further research is necessary to fully elucidate the underlying molecular pathways and optimize treatment strategies, the findings presented in this study offer hope for improved outcomes in patients with Doxorubicin-resistant AML. By continuing to explore the potential of novel agents like MIA-602, the scientific community moves closer to achieving the ultimate goal of personalized, effective, and well-tolerated treatments for this challenging malignancy.

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.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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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).

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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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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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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Trending With Impact: Dual Requirement in Stem Cell Leukemia/Lymphoma

May 13, 2022

For the first time, researchers revealed the protein interactome, phospho-proteome and total proteome for the oncogenic fusion protein BCR-FGFR1.

Figure 6: Signaling pathways activated by BCR-FGFR1.

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Chromosomes are found in the nucleus of cells and consist of proteins and tightly coiled strands of DNA. During cell division, chromosomal translocations can occur while the chromosomes are being copied. This type of mutation can mean that an entire chromosome has moved to another location, or that a chromosome has broken, usually into two pieces, and moved to another site. Some translocations are harmless, but others can lead to aberrant cell proliferation and cancer.

“Over the last half century, chromosomal translocations encoding functional oncogenic proteins have been identified as drivers of multiple cancers, and account for 20% of all malignant neoplasms [1, 2].”

For example, the t(8;22)(p11;q11) chromosomal translocation leads to the initiation of an oncogenic fusion protein called the Breakpoint Cluster Region Fibroblast Growth Factor Receptor 1 (BCR-FGFR1). BCR-FGFR1 is a single driver of 8p11 myeloproliferative syndrome, which is also known as stem cell leukemia/lymphoma (SCLL).

“Stem cell leukemia/lymphoma (SCLL) exhibits distinct clinical and pathological features characterized by chromosomal translocations involving the FGFR1 gene at chromosome 8p11.”

In a trending new study, researchers from the University of California San Diego and Sanford Burnham Prebys Medical Discovery Institute examined mutations in PLCγ1 and Grb2 binding sites individually and when combined together in a double mutant within BCR-FGFR1. On May 11, 2022, the research paper was published in Oncotarget and entitled, “Proteomic analysis reveals dual requirement for Grb2 and PLCγ1 interactions for BCR-FGFR1-Driven 8p11 cell proliferation.”

The Study

In this study, the researchers used quantitative proteomic analyses to identify the crucial protein-to-protein interactions that may be necessary to activate BCR-FGFR1. The team used NIH3T3, HEK293T and 32D cells to assay five types of mutations: wild type BCR-FGFR1, a kinase-dead variant of BCR-FGFR1, a derivative of BCR-FGFR1 that contained a single mutation abolishing the Grb2 interaction site, a derivative of BCR-FGFR1 that contained a single mutation abolishing the PLCγ1 interaction site, and a double mutation that abolished both interaction sites (BCR(Y177F)-FGFR1(Y766F)).

“These data demonstrate that inhibition of either signaling pathway alone fails to inhibit hematopoietic cell proliferation, and demonstrate a dual requirement for Grb2 and PLCγ1 interactions with BCR-FGFR1 for proliferation.”

When either Grb2 or PLCγ1 signaling pathway was mutated, BCR-FGFR1 activity was decreased, but never abolished. However, when both Grb2 and PLCγ1 interactions were mutated, both cell transformation and proliferation were inhibited. The team demonstrated that BCR-FGFR1 dually relies on Grb2 and PLCγ1 for biological activity and the activation of cell signaling pathways. The researchers also found that the PLCγ1 inhibitor U73122 revealed that PLCγ1 is a potential therapeutic target for BCR-FGFR1-driven hematologic malignancies. In addition, the irreversible FGFR inhibitor futibatinib suppressed downstream signaling and cell transformation.

“We demonstrate here that BCR-FGFR1 relies dually on the small adapter protein, Grb2, and the phospholipase, PLCγ1, for biological activity and the activation of cell signaling pathways (summarized in Figure 6).”

Conclusion

“Our work highlights the importance of sequencing based, mutation-specific therapies for FGFR1 induced hematologic malignancies.”

This study provides new insight into the potential molecular mechanisms underlying BCR-FGFR1 activity and identifies PLCγ1 as a therapeutic target for leukemia/lymphoma patients with this particular mutation. Future studies will be necessary to validate these findings in animal models and clinical trials. However, this study lays the groundwork for the development of new and more targeted leukemia/lymphoma therapies.

“These data unravel essential roles of Grb2 and PLCγ1 in BCR-FGFR1 mediated oncogenic growth and suggest the importance of further investigation into PLCγ1 as a potential therapeutic target in treating SCLL.”

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

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Trending with Impact: Acute Myeloid Leukemia and Midostaurin Response

April 23, 2021

Researchers examined midostaurin resistance or sensitivity in a cohort of patients with acute myeloid leukemia.

Figure 2: Differential gene expression for midostaurin sensitive vs. resistant samples identifies a unique signature. — **Figure 2:** Differential gene expression for midostaurin sensitive vs. resistant samples identifies a unique signature.

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Acute myeloid leukemia (AML) is a heterogeneous malignancy that most commonly affects older adults, 60 years of age and older. NPM1, DNMT3A, and FLT3 are the most common genomic alterations found within this disease. In about 30% of AML patients, FLT3 is mutated. Midostaurin was the first FDA approved FLT3 inhibitor for AML. While Midostaurin has a successful overall survival benefit, both primary and secondary resistance remains common.

“A subtype of AML, classified by the presence of a FLT3-Internal Tandem Duplication (ITD) mutation, tends to have a worse prognosis with early relapse and death [5].”

Researchers from Oregon Health and Science University and Howard Hughes Medical Institute conducted a study to identify features that may predict response to midostaurin in FLT3 mutant and wild-type samples. They performed an ex vivo drug sensitivity screen on primary and relapsed AML samples, with corresponding targeted sequencing and RNA sequencing. The paper was entitled: “Genomic markers of midostaurin drug sensitivity in FLT3 mutated and FLT3 wild-type acute myeloid leukemia patients.”

The Study

In order to understand the impact that different genomic alterations have on midostaurin response, 214 patients were functionally assessed with midostaurin and their FLT3 status was annotated. Of these patients, the researcher identified 193 primary and 21 relapse AML samples from the Beat AML publicly available dataset. Risk groups within the cohort were as follows: 73 samples were favorable risk, 59 samples were intermediate, and 68 were adverse. The median age of patients in the cohort was 61, with 52% male and 48% female.

“We hypothesized that there are additional genomic alterations and gene expression changes outside of FLT3-ITD mutations that can influence AML sample resistance or sensitivity to midostaurin and aimed to further characterize these factors.”

Drug sensitivity screening, RNA sequencing/expression analysis, custom gene panel (GeneTrails) sequencing and variant detection, exome sequencing and variant detection, internal FLT3-ITD and NPM1 mutation detection, derivation of FLT3-ITD and NPM1 consensus calls, ex vivo functional drug screens, and statistical analysis were the methods used to observe the impact of genomic alterations on midostaurin response.

“Our research explored the multi-targeted nature of midostaurin and suggested a number of molecular mutational patterns that correlated with midostaurin drug sensitivity and resistance in both FLT3-ITD mutated and FLT3-ITD wild-type AML patient samples.”

Results

The researchers observed specific point mutations and gene expression patterns that they believe explain why there is a range of responses to midostaurin treatment. In the FLT3-ITD positive cohort, increased expression of the oncogene RGL4 (and regulator of the Ras-Raf-MEK-ERK cascade) correlated with poorer midostaurin response. In the FLT3-ITD negative cohort, KRAS mutations correlated with a poorer midostaurin response.

“We also observed that 16 / 34 of the most sensitive samples did not harbor a FLT3 mutation and a majority of differentially expressed genes were independent of FLT3 status.”

Conclusion

The authors point out that additional research studies will be needed given that their sample cohort was relatively small. They also note that since there are multiple FLT3 inhibitors available, it is important to understand the sensitivity mechanisms of each intervention in order to better personalize therapy for chemo-refractory or relapsed AML patients.

“Overall, we identify genomic alterations that correlate with midostaurin response independent of FLT3-ITD status, propose that Ras-Raf-MEK-ERK inhibition in combination therapy could limit resistance to midostaurin, and suggest that within the overall AML population there may be therapeutic benefit of midostaurin in patients with certain expression profiles.”

Click here to read the full scientific study, published in Oncotarget.

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