scholarly journals Early Detection is as Important as Imatinib in CML Treatment Success

Author(s):  
Dmitriy Sonkin ◽  
Richard Simon

Chronic myelogenous leukemia (CML) was the first malignancy for which clinical outcome was drastically improved by kinase inhibitor therapy. Kinase inhibitors targeting other well-known oncogenes have been introduced into clinical practice, but none have shown the same magnitude of clinical benefit as ABL1 inhibition in CML. We argue that early detection is an underappreciated, but critically important factor in success of ABL1 inhibitors in treatment of CML. We show that CML provides a window into how many types of cancer may look and behave at an early stage, prior to diagnosis and the development of additional genomic alterations. The remarkable clinical benefits of ABL1 inhibition is likely due to early detection of CML at a stage in which the tumor is driven by single oncogenic alteration which can be successfully controlled by the inhibitor. Thinking of CML as a prototype for effective systemic treatment based on early cancer detection may help to develop strategies for improving treatment for other types of cancer.

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hu Lei ◽  
Han-Zhang Xu ◽  
Hui-Zhuang Shan ◽  
Meng Liu ◽  
Ying Lu ◽  
...  

AbstractIdentifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.


2021 ◽  
Author(s):  
Lin Huang ◽  
Kun Qian

Abstract Early cancer detection greatly increases the chances for successful treatment, but available diagnostics for some tumours, including lung adenocarcinoma (LA), are limited. An ideal early-stage diagnosis of LA for large-scale clinical use must address quick detection, low invasiveness, and high performance. Here, we conduct machine learning of serum metabolic patterns to detect early-stage LA. We extract direct metabolic patterns by the optimized ferric particle-assisted laser desorption/ionization mass spectrometry within 1 second using only 50 nL of serum. We define a metabolic range of 100-400 Da with 143 m/z features. We diagnose early-stage LA with sensitivity~70-90% and specificity~90-93% through the sparse regression machine learning of patterns. We identify a biomarker panel of seven metabolites and relevant pathways to distinguish early-stage LA from controls (p < 0.05). Our approach advances the design of metabolic analysis for early cancer detection and holds promise as an efficient test for low-cost rollout to clinics.


Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3958-3961 ◽  
Author(s):  
Jörg Cammenga ◽  
Stefan Horn ◽  
Ulla Bergholz ◽  
Gunhild Sommer ◽  
Peter Besmer ◽  
...  

Multiple genetic alterations are required to induce acute myelogenous leukemia (AML). Mutations in the extracellular domain of the KIT receptor are almost exclusively found in patients with AML carrying translocations or inversions affecting members of the core binding factor (CBF) gene family and correlate with a high risk of relapse. We demonstrate that these complex insertion and deletion mutations lead to constitutive activation of the KIT receptor, which induces factor-independent growth of interleukin-3 (IL-3)–dependent cells. Mutation of the evolutionary conserved amino acid D419 within the extracellular domain was sufficient to constitutively activate the KIT receptor, although high expression levels were required. Dose-dependent growth inhibition and apoptosis were observed using either the protein tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) or by blocking the phosphoinositide-3-kinase (PI3K)–AKT pathway. Our data show that the addition of kinase inhibitors to conventional chemotherapy might be a new therapeutic option for CBF-AML expressing mutant KIT.


2015 ◽  
Vol 4 (2S) ◽  
pp. 17-20
Author(s):  
Mario Annunziata

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.


2018 ◽  
Vol 4 (Supplement 3) ◽  
pp. 26s-26s
Author(s):  
Carlos Munoz-Zuluaga ◽  
Armando Sardi ◽  
Mavalynne Orozco-Urdaneta ◽  
Luis Gabriel Parra-Lara ◽  
Andres Perez ◽  
...  

Purpose For Colombian women, breast and cervical cancer are the leading causes of mortality, despite being potentially curable through early detection and timely treatment. Tedious administrative processes and a lack of cancer screening education and awareness hinders early detection. Mobile applications (mApps) have permeated all levels of society and are potential tools by which to deliver personalized information and identify high-risk patients in need of screening tests thereby improving early cancer detection. The aim of this work is to create a free mApp that educates and guides patients to the national screening programs for breast and cervical cancer. Methods An mApp Amate was advertised to women (age ≥ 14 years) in the waiting rooms of a health care facility of a community hospital during a period of 9 months. Amate used educational, evaluative, and risk factor questions to measure the population’s knowledge of breast and cervical cancer. Each question was followed by an explanation. Correct answers yielded points that were redeemable for cellular data. Risk assessment questions identified women who required screening who were subsequently contacted by a health care provider and enrolled in the national cancer care program. Results A total of 4,553 women were contacted from August 2017 to May 2018. Of this group, 830 downloaded Amate and answered all of the questions. On the basis of the risk factor questions, 16% of patients (n = 131) were identified as being at risk for breast and/or cervical cancer and needed to be enrolled in the national screening program. Thus far, 24% of patients (n = 32) have successfully completed their recommended screening tests—mammogram, Papanicolau smear, or both. We also identified specific barriers to enrolling patients in these programs, including an unwillingness to be enrolled, limited available appointments at health care centers, and denied access as a result of health care coverage. Conclusion Amate is a low-cost, accessible tool that identifies women who are at risk for breast and cervical cancer and detects access barriers to early cancer detection. Administrative obstacles still exist and must be addressed to improve early cancer detection and screening. Amate has the potential to reach people from rural areas of Colombia and other underserved countries. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc . Armando Sardi Stock or Other Ownership: Celgene, Johnson & Johnson Mavalynne Orozco-Urdaneta Employment: Partners For Cancer Care And Prevention Foundation, Stamina-in-Action Stock or Other Ownership: Celgene, Johnson & Johnson Luis Gabriel Parra-Lara Research Funding: Merk & Co


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 652-652 ◽  
Author(s):  
Paul La Rosee ◽  
Nicolai Haertel ◽  
Thomas Klag ◽  
Heiko Konig ◽  
Ruediger Hehlmann ◽  
...  

Abstract The BCR-ABL oncoprotein promotes growth and survival by activating Ras-dependent MAPK-signalling, which can be blocked by the Abl-kinase inhibitor imatinib, the current standard treatment for chronic myelogenous leukemia (CML). However, paradoxical MAPK-activation is observed in CD34+ progenitor cells of CML patients when exposed to imatinib in the presence of growth factors. Cytokine-dependent MAPK-activation may underlie primary resistance of the leukemic stem cell to imatinib. Second generation BCR-ABL inhibitors have been developed, but their potential to modulate the MAPK has not been evaluated. Here we demonstrate differential MAPK-modulating activity of currently available ABL-inhibitors and report a cell line model mimicking paradoxical, cytokine dependent MAPK-activation in response to BCR-ABL-inhibition. CD34+ enriched mononuclear cells (MNC) derived from CML patients prior to treatment (n=5) were cultured in serum-free media in the presence of standard growth factor mix (GF). Overnight exposure of single agent or combined inhibitors (nilotinib, dasatinib), and subsequent analysis of MAPK-activation was performed. BCR-ABL-transformed Baf3 and 32D cells were grown in the presence of increasing concentrations of tyrosine kinase inhibitors up to 24 hrs. Cultures were kept either with or without Interleukin 3 (IL3). Signaling was studied after SDS-page of whole cell lysates and subsequent Western blot analysis. Inhibitor isodoses were determined using tetrazolium based proliferation assays. Results: CD34+ CML MNC show significant and dose dependent activation of MAPK1/2 in response to nilotinib ([fold change of control]; 0.2μM: 2.7±1.1, p<0.05; 1.0μM: 3.2±1.2, p<0.05). Co-treatment with imatinib tends to enhance the MAPK-activation seen with nilotinib alone. In contrast, exposure of patient cells (n=5) to dasatinib results in a significant MAPK-inhibition (12nM: 0.4±0.3, p<0.05; 60nM: 0.5±0.3, p<0.05). However, combined application of nilotinib with dasatinib overrides the MAPK-inhibitory activity of dasatinib (dasatinib: 0.4±0.3, p<0.05 vs dasatinib+nilotinib: 2.3±2; n.s.). The myeloid 32Dp210 cells when grown in the presence of IL3 reflect the results seen in primary cells with activation of MAPK1/2 in the presence of nilotinib. Time course experiments show peak-activation at 6hrs after start of treatment (0.04μM: 2.8±1.6, n.s.; 0.2μM: 2.8±1.9; n.s.). Without IL3, MAPK’s are significantly inhibited confirming the cytokine-dependence of MAPK-activation (p<0.05). This contrasts data obtained with dasatinib, which leads to MAPK-inhibition even in the presence of IL3 (12nM: 0.5±0.2, n.s., 60nM: 0.5±0.1, n.s.). In lymphoid Bafp210, nilotinib and dasatinib both effectively inhibit MAPK1/2 even in the presence of IL3, demonstrating cell context dependent MAPK-modulation in response to Abl-kinase-inhibitors. Conclusions: Nilotinib induces significant MAPK1/2-activation in CD34+ CML progenitors similar to previously reported results with imatinib. Effective MAPK-inhibition in CD34+ cells by dasatinib may underlie a possible higher stem cell activity of dasatinib. Reversal of MAPK-inhibition in combination experiments indicates that nilotinib acts through mechanisms that cannot be influenced by dasatinib. 32Dp210 cells may prove useful to study the exact mechanisms of paradoxical MAPK-activation.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1669-1669
Author(s):  
Franck E. Nicolini ◽  
Françoise Huguet ◽  
Hélène Labussière-Wallet ◽  
Yann Guillermin ◽  
Madeleine Etienne ◽  
...  

Abstract Abstract 1669 Most epidemiologic studies performed in chronic myelogenous leukemia (CML) relate that the disease occurs preferentially in males with a sex ratio of ∼1.2. In addition, CML can be diagnosed in young adults and masculine fertility is a matter of concern, particularly because tyrosine kinase inhibitors (TKI) may impact on spermatogenesis by a selective inhibition of Src kinases, PDGF-R and c-kit. Sperm cryopreservation is recommended by some authors at diagnosis in males that would expect to have children later on. In a retrospective analysis we have analysed the spermograms of 62 chronic phase (CP) and 2 onset blast crisis (BC) CML males referred to our 3 centres between 2001 and 2012, collected at diagnosis before TKI treatment, and we have compared the results obtained to those of 15 healthy volunteer donors from the cryopreservation bank database, after informed consent. In 10 patients we could collect some data for patients being on imatinib mesylate (IM). CML patients had a median age of 31 (16–48) years, significantly younger than that in the control group of healthy donors: 37 (34–45) years (p=0.001). Sokal scores were 24% high, 27% intermediate and 49% low for evaluable patients (13 patients unknown or not available). The median BCR-ABLIS value at diagnosis was 77.65%. Patients had a median duration of 26 (0–38) days of hydroxyurea prior to commencing any TKI and 65% of evaluable patients had HU before TKI. None of the patients got interferon prior to TKI. The semen cryopreservation was performed within a median of 10 (2–102) days after CML diagnosis and after a median abstinence of 5 (0.5–30) days. The median volume of semen obtained in CML patients was 2.95 (0.5–14.9) ml and 3 (1.4–5.3) ml for normal donors (p=0.3). Williams test showed 72 (0–87)% of necrospermia in patients versus 18 (4–32)% in donors (p=0.00003). The median number of spermatozoa obtained was not different in patients [46 (0.03–200) 106/ml] than that in donors [74 (19.2–253) 106/ml] (p=0.24), as well as the number of spermatozoa per ejaculate observed (p=0.49). The motility of spermatozoa at 30 minutes after collection was not different between patients (median = 47.5%) and donors (median = 50%) (p=0.12), however higher numbers of atypical spermatozoa were observed in patients [median = 77.5 (16–100)%] rather than in donors [median = 45% (22–89)%], p=0.008, and the multiple abnormalities index (MAI) was significantly higher in patients [median = 1.99 (1.14–2.7)] than that in donors [median = 1.33 (1.09–1.55)], p=0.00006. There was no correlation between age at diagnosis, Sokal index and the number of spermatozoa per ml obtained (p=0.7 and 0.21 respectively). Ten CP CML patients had spermograms after a median of 1440 (9–1456) days of IM treatment and the results obtained were compared to i) the results of each individual patient at CP diagnosis and ii) to the results of healthy comparators. In comparison to the characteristics observed at diagnosis, the semen volume (median = 3.1 ml), Williams test (median = 65%), the motility at 30 minutes (median = 37.5%) and the MAI (median = 1.71) were not different (p=ns for all), however, the numbers of spermatozoa (median = 14.9 106/ml and = 37.05 ml per ejaculate) collected on IM were significantly lower (p=0.014 and p=0.045 respectively). The different parameters evaluated on IM were compared to those of normal controls and showed significant alterations. The semen volume was not different (p=0.94), neither the motility of spermatozoa (p=0.24), but the Williams test was highly perturbed on IM [median 65 (24–79)% versus 18 (4–32)% in donors] p=0.00003, as well as the numbers of spermatozoa as 106 per ml, collected on IM [median 14.9 (0.67–179)) versus normal [74 (19.2–253)], p=0.0036 or as 106 per ejaculate collected on IM [median 37.5 (2.68–572.8)) versus normal [149 (30–535.3)], p=0.026. Atypical forms were significantly more abundant on IM [median = 80 (68–90)%] versus healthy controls [median = 45% (22–89)], p=0.0058. Finally, the MAI was severely altered on IM [median = 1.71 (1.61–1.98)] versus normal individuals [median = 1.33 (1.09–1.55)], p=0.00013. In conclusion, this work demonstrates the existence of significant sperm alterations in young males with CML at diagnosis of undetermined origin, prior to any treatment. These alterations persist on IM treatment and little is know about the impact of second generation TKI. Thus the most appropriate approach remains a matter of debate in thus setting. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huguet:Novartis, BMS: Speakers Bureau. Michallet:Novartis, Pfizer, Teva, Genzyme, Janssen Cilag, BMS, Merck, Pfizer, Gilead, Alexion: Consultancy, Speakers Bureau. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy.


Author(s):  
Michael J. Mauro

Resistance in chronic myelogenous leukemia is an issue that has developed in parallel to the availability of rationally designed small molecule tyrosine kinase inhibitors to treat the disease. A significant fraction of patients with clinical resistance are recognized to harbor point mutations/substitutions in the Abl kinase domain, which limit or preclude drug binding and activity. Recent data suggest that compound mutations may develop as well. Proper identification of clinical resistance and prudent screening for all causes of resistance, ranging from adherence to therapy to Abl kinase mutations, is crucial to success with kinase inhibitor therapy. There is currently an array of Abl kinase inhibitors with unique toxicity and activity profiles available, allowing for individualizing therapy beginning with initial choice at diagnosis and as well informed choice of subsequent therapy in the face of toxicity or resistance, with or without Abl kinase domain mutations. Recent studies continue to highlight the merits of increasingly aggressive initial therapy to subvert resistance and importance of early response to identify need for change in therapy. Proper knowledge and navigation amongst novel therapy options and consideration of drug toxicities, individual patient characteristics, disease response, and vigilance for development of resistance are necessary elements of optimized care for the patient with chronic myelogenous leukemia.


Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 497-499 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Claude Nicaise ◽  
Susan O'Brien ◽  
...  

Abstract Developing strategies to counteract imatinib resistance constitutes a challenge in chronic myelogenous leukemia (CML). Therapy with the tyrosine kinase inhibitors nilotinib (AMN107) and dasatinib (BMS-354825) has produced high rates of hematologic and cytogenetic response. Src kinase activation has been linked to Bcr-Abl–mediated leukemogenesis and CML progression. In addition to binding Abl kinase with less stringent conformational requirements than imatinib, dasatinib is a potent Src kinase inhibitor. In the current study, we report on 23 patients with CML (19 of them in accelerated or blastic phases) treated with dasatinib after treatment failure with both imatinib and nilotinib. More than half (13; 57%) of 23 patients responded to dasatinib: 10 (43%) had a complete hematologic response (CHR), including 7 (30%) who had a cytogenetic response (2 complete, 4 partial, and 1 minor). These results suggest that dasatinib may be active in some patients after failure with both imatinib and nilotinib.


2021 ◽  
Author(s):  
Grigorii V. Andrianov ◽  
Wern Juin Gabriel Ong ◽  
Ilya Serebriiskii ◽  
John Karanicolas

In early stage drug discovery, the stage of hit-to-lead optimization (or "hit expansion") entails starting from a newly-identified active compound, and improving its potency or other properties. Traditionally this process relies on synthesizing and evaluating a series of analogs to build up structure-activity relationships. Here, we describe a computational strategy focused on kinase inhibitors, intended to expedite the process of identifying analogs with improved potency. Our protocol begins from an inhibitor of the target kinase, and generalizes the synthetic route used to access it. By searching for commercially-available replacements for the individual building blocks used to make the parent inhibitor, we compile an enumerated library of compounds that can be accessed using the same chemical transformations; these huge libraries can exceed many millions - or billions - of compounds. Because the resulting libraries are much too large for explicit virtual screening, we instead consider alternate approaches to identify the top-scoring compounds. We find that contributions from individual substituents are well-described by a pairwise additivity approximation, provided that the corresponding fragments position their shared core in precisely the same way relative to the binding site. This key insight allows us to determine which fragments are suitable for merging into a single new compounds, and which are not. Further, the use of the pairwise approximation allows interaction energies to be assigned to each compound in the library, without the need for any further structure-based modeling: interaction energies instead can be reliably estimated from the energies of the component fragments. We demonstrate this protocol using libraries built from five representative kinase inhibitors drawn from the literature, which target four different kinases: CDK9, CHK1, CDK2, and ACK1. In each example, the enumerated library includes additional analogs reported by the original study to have activity, and these analogs are successfully prioritized within the library. We envision that the insights from this work can facilitate the rapid assembly and screening of increasingly large libraries for focused hit-to-lead optimization. To enable adoption of these methods and to encourage further analyses, we disseminate the computational tools needed to deploy this protocol.


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