Publications by authors named "Varsha Gandhi"

201 Publications

Ibrutinib combinations in CLL therapy: scientific rationale and clinical results.

Blood Cancer J 2021 Apr 29;11(4):79. Epub 2021 Apr 29.

Departments of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). This drug irreversibly inhibits Bruton tyrosine kinase (BTK) by covalently binding to the C481 residue in the BTK kinase domain. BTK is a pivotal protein for B cell receptor signaling and tissue homing of CLL cells. Preclinical investigations have established the importance of the B cell receptor pathway in the maintenance and survival of normal and malignant B cells, underscoring the importance of targeting this axis for CLL. Clinical trials demonstrated overall and progression-free survival benefit with ibrutinib in multiple CLL subgroups, including patients with relapsed or refractory disease, patients with 17p deletion, elderly patients, and treatment-naïve patients. Consequently, ibrutinib was approved by the US Food and Drug Administration for newly diagnosed and relapsed disease. Ibrutinib has transformed the treatment of CLL; however, several limitations have been identified, including low complete remission rates, development of resistance, and uncommon substantial toxicities. Further, ibrutinib must be used until disease progression, which imposes a financial burden on patients and society. These limitations were the impetus for the development of ibrutinib combinations. Four strategies have been tested in recent years: combinations of ibrutinib with immunotherapy, chemoimmunotherapy, cell therapy, and other targeted therapy. Here, we review the scientific rationale for and clinical outcome of each strategy. Among these strategies, ibrutinib with targeted agent venetoclax results in high complete response rates and, importantly, high rates of undetectable minimal residual disease. Although we concentrate here on ibrutinib, similar combinations are expected or ongoing with acalabrutinib, tirabrutinib, and zanubrutinib, second-generation BTK inhibitors. Future investigations will focus on the feasibility of discontinuing ibrutinib combinations after a defined time; the therapeutic benefit of adding a third agent to ibrutinib-containing combinations; and profiling of resistant clones that develop after combination treatment. A new standard of care for CLL is expected to emerge from these investigations.
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http://dx.doi.org/10.1038/s41408-021-00467-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085243PMC
April 2021

Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine.

J Hematol Oncol 2021 Apr 26;14(1):70. Epub 2021 Apr 26.

Hematology Malignancies Research Institute, Gehr Family Center for Leukemia Research, City of Hope Medical Center, Kaplan CRB, 1026, 1500 East Duarte Road, Duarte, CA, 91010, USA.

Background: BCL-2 inhibition through venetoclax (VEN) targets acute myeloid leukemia (AML) blast cells and leukemic stem cells (LSCs). Although VEN-containing regimens yield 60-70% clinical response rates, the vast majority of patients inevitably suffer disease relapse, likely because of the persistence of drug-resistant LSCs. We previously reported preclinical activity of the ribonucleoside analog 8-chloro-adenosine (8-Cl-Ado) against AML blast cells and LSCs. Moreover, our ongoing phase I clinical trial of 8-Cl-Ado in patients with refractory/relapsed AML demonstrates encouraging clinical benefit. Of note, LSCs uniquely depend on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. VEN inhibits OXPHOS in LSCs, which eventually may escape the antileukemic activity of this drug. FAO is activated in LSCs isolated from patients with relapsed AML.

Methods: Using AML cell lines and LSC-enriched blast cells from pre-treatment AML patients, we evaluated the effects of 8-Cl-Ado, VEN and the 8-Cl-Ado/VEN combination on fatty acid metabolism, glycolysis and OXPHOS using liquid scintillation counting, a Seahorse XF Analyzer and gene set enrichment analysis (GSEA). Western blotting was used to validate results from GSEA. HPLC was used to measure intracellular accumulation of 8-Cl-ATP, the cytotoxic metabolite of 8-Cl-Ado. To quantify drug synergy, we created combination index plots using CompuSyn software. The log-rank Kaplan-Meier survival test was used to compare the survival distributions of the different treatment groups in a xenograft mouse model of AML.

Results: We here report that VEN and 8-Cl-Ado synergistically inhibited in vitro growth of AML cells. Furthermore, immunodeficient mice engrafted with MV4-11-Luc AML cells and treated with the combination of VEN plus 8-Cl-Ado had a significantly longer survival than mice treated with either drugs alone (p ≤ 0.006). We show here that 8-Cl-Ado in the LSC-enriched population suppressed FAO by downregulating gene expression of proteins involved in this pathway and significantly inhibited the oxygen consumption rate (OCR), an indicator of OXPHOS. By combining 8-Cl-Ado with VEN, we observed complete inhibition of OCR, suggesting this drug combination cooperates in targeting OXPHOS and the metabolic homeostasis of AML cells.

Conclusion: Taken together, the results suggest that 8-Cl-Ado enhances the antileukemic activity of VEN and that this combination represents a promising therapeutic regimen for treatment of AML.
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http://dx.doi.org/10.1186/s13045-021-01076-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074444PMC
April 2021

Managing chronic lymphocytic leukemia in 2020: an update on recent clinical advances with a focus on BTK and BCL-2 inhibitors.

Fac Rev 2021 26;10:22. Epub 2021 Feb 26.

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

The therapeutic landscape of chronic lymphocytic leukemia (CLL) underwent a paradigm shift in 2014 with the approval of ibrutinib, which binds covalently to the C481 residue of Bruton's tyrosine kinase (BTK) and irreversibly inhibits it. A number of large, phase 3 trials conducted in both the frontline and the relapsed/refractory settings resulted in the approval of ibrutinib for all CLL. Indeed, the role of chemoimmunotherapy in CLL is fast dwindling. The limitations of ibrutinib, e.g. the development of resistance-conferring C481 BTK mutations and the toxicity issues of atrial fibrillation and bleeding, in particular, have also become apparent with longer-term follow-up. This has spurred the development of second-generation, irreversible inhibitors with greater selectivity for BTK and third-generation, reversible BTK inhibitors to address C481 site mutations. The last 3 years have also witnessed enormous growth in the therapeutic role of the B-cell lymphoma 2 (BCL-2) antagonist venetoclax, initially approved (in 2016) only for patients with relapsed, 17p-deleted CLL. Venetoclax, in combination with CD20 antibodies, is currently approved for both treatment-naïve and relapsed/refractory patients, regardless of genomic subtype. Robust results have also been reported for ibrutinib plus venetoclax, and "triple" combinations of a BTK inhibitor, venetoclax, and obinutuzumab are now being pursued. The major questions facing the field at present are how best to select patients for BTK inhibitor monotherapy versus venetoclax/obinutuzumab upfront, what to do after failure of both BTK inhibitor(s) and venetoclax, and the ideal way to integrate measurable residual disease data into decisions regarding treatment choice, duration, and discontinuation.
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http://dx.doi.org/10.12703/r/10-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946394PMC
February 2021

Metabolism meets apoptosis in AML.

Leuk Lymphoma 2021 03 25;62(3):514-516. Epub 2020 Dec 25.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1080/10428194.2020.1858294DOI Listing
March 2021

Activation of ATM kinase by ROS generated during ionophore-induced mitophagy in human T and B cell malignancies.

Mol Cell Biochem 2021 Jan 29;476(1):417-423. Epub 2020 Sep 29.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Unit 1950, 1901 East Road, Houston, TX, 77054, USA.

Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor, also possesses non-nuclear functions owing to its presence in extra-nuclear compartments, including peroxisomes, lysosomes, and mitochondria. ATM is frequently altered in several human cancers. Recently, we and others have shown that loss of ATM is associated with defective mitochondrial autophagy (mitophagy) in ataxia-telangiectasia (A-T) fibroblasts and B-cell lymphomas. Further, we reported that ATM protein but not ATM kinase activity is required for mitophagy. However, the mechanism of ATM kinase activation during ionophore-induced mitophagy is unknown. In the work reported here, using several ionophores in A-T and multiple T-cell and B-cell lymphoma cell lines, we show that ionophore-induced mitophagy triggers oxidative stress-induced ATM phosphorylation through ROS activation, which is different from neocarzinostatin-induced activation of ATM, Smc1, and Kap1. We used A-T cells overexpressed with WT or S1981A (auto-phosphorylation dead) ATM plasmids and show that ATM is activated by ROS-induced oxidative stress emanating from ionophore-induced mitochondrial damage and mitophagy. The antioxidants N-acetylcysteine and glutathione significantly inhibited ROS production and ATM phosphorylation but failed to inhibit mitophagy as determined by retroviral infection with mt-mKeima construct followed by lysosomal dual-excitation ratiometric pH measurements. Our data suggest that while ATM kinase does not participate in mitophagy, it is activated via elevated ROS.
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http://dx.doi.org/10.1007/s11010-020-03917-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867566PMC
January 2021

A systematic review exploring the evidence reported to underpin exercise dose in clinical trials of rheumatoid arthritis.

Rheumatology (Oxford) 2020 11;59(11):3147-3157

Department of Clinical Sciences, Brunel University London, Uxbridge, UK.

We aimed to evaluate the evidence reported to underpin exercise dose in randomised controlled trials (RCTs) using strengthening exercise in RA. We searched six different databases between 1 January 2000 and 3 April 2019. We included RCTs, where a main component of the intervention and/or control used strengthening exercise. Evidence sources cited to underpin dose were judged for their quality, consistency and applicability. Thirty-two RCTs were reviewed. Four (12.5%) piloted the intervention without using dose-escalation designs to determine optimal dose-response. Twenty (62.5%) reported no evidence underpinning dose. Where reported, quality, consistency and applicability of the underpinning evidence was a cause for methodological concern. The majority of RCTs did not report the evidence underpinning dose. When reported, the evidence was often not applicable to the clinical population. Frequently, the dose used differed to the dose reported/recommended by the underpinning evidence. Our findings illustrate exercise dose may not be optimised for use with clinical populations prior to evaluation by RCT.
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http://dx.doi.org/10.1093/rheumatology/keaa150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590408PMC
November 2020

Ataxia-telangiectasia mutated interacts with Parkin and induces mitophagy independent of kinase activity. Evidence from mantle cell lymphoma.

Haematologica 2021 Feb 1;106(2):495-512. Epub 2021 Feb 1.

MD Anderson Cancer Center.

Ataxia telangiectasia mutated (ATM), a critical DNA damage sensor with protein kinase activity,is frequently altered in human cancers including mantle cell lymphoma (MCL). Loss of ATM protein is linked to accumulation of nonfunctional mitochondria and defective mitophagy, in both murine thymocytes and in A-T cells. However, the mechanistic role of ATM kinase in cancer cell mitophagy is unknown. Here, we provide evidence that FCCP-induced mitophagy in MCL and other cancer cell lines is dependent on ATM but independent of its kinase function. While Granta-519 MCL cells possess single copy and kinase dead ATM and are resistant to FCCP-induced mitophagy, both Jeko-1 and Mino cells are ATM proficient and induce mitophagy. Stable knockdown of ATM in Jeko-1 and Mino cells conferred resistance to mitophagy and was associated with reduced ATP production, oxygen consumption, and increased mROS. ATM interacts with the E3 ubiquitin ligase Parkin in a kinase-independent manner. Knockdown of ATM in HeLa cells resulted in proteasomal degradation of GFP-Parkin which was rescued by the proteasome inhibitor, MG132 suggesting that ATM-Parkin interaction is important for Parkin stability. Neither loss of ATM kinase activity in primary B cell lymphomas nor inhibition of ATM kinase in MCL, A-T and HeLa cell lines mitigated FCCP or CCCP-induced mitophagy suggesting that ATM kinase activity is dispensable for mitophagy. Malignant B-cell lymphomas without detectable ATM, Parkin, Pink1, and Parkin-Ub ser65 phosphorylation were resistant to mitophagy, providing the first molecular evidence of ATM's role in mitophagy in MCL and other B-cell lymphomas.
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http://dx.doi.org/10.3324/haematol.2019.234385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849759PMC
February 2021

AMG-176, an Mcl-1 Antagonist, Shows Preclinical Efficacy in Chronic Lymphocytic Leukemia.

Clin Cancer Res 2020 07 14;26(14):3856-3867. Epub 2020 Jan 14.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Survival of CLL cells due to the presence of Bcl-2 and Mcl-1 has been established. Direct inhibition of Bcl-2 by venetoclax and indirect targeting of Mcl-1 with transcription inhibitors have been successful approaches for CLL. AMG-176 is a selective and direct antagonist of Mcl-1, which has shown efficacy in several hematologic malignancies; however, its effect on CLL is elusive. We evaluated biological and molecular effects of AMG-176 in primary CLL cells.

Experimental Design: Using samples from patients ( = 74) with CLL, we tested effects of AMG-176 on CLL and normal hematopoietic cell death and compared importance of CLL prognostic factors on this biological activity. We evaluated CLL cell apoptosis in the presence of stromal cells and identified cell death pathway including stabilization of Mcl-1 protein. Finally, we tested a couplet of AMG-176 and venetoclax in CLL lymphocytes.

Results: AMG-176 incubations resulted in time- and dose-dependent CLL cell death. At 100 and 300 nmol/L, there was 30% and 45% cell death at 24 hours. These concentrations did not result in significant cell death in normal hematopoietic cells. Presence of stroma did not affect AMG-176-induced CLL cell death. IGHV unmutated status, high β2M and Mcl-1 protein levels resulted in slightly lower cell death. Mcl-1, but not Bcl-2 protein levels, in CLL cells increased with AMG-176. Low concentrations of venetoclax (1-30 nmol/L) were additive or synergistic with AMG-176.

Conclusions: AMG-176 is active in inducing CLL cell death while sparing normal blood cells. Combination with low-dose venetoclax was additive or synergistic.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358119PMC
July 2020

Trabectedin Reveals a Strategy of Immunomodulation in Chronic Lymphocytic Leukemia.

Cancer Immunol Res 2019 12 17;7(12):2036-2051. Epub 2019 Sep 17.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Chronic lymphocytic leukemia (CLL) is a B-cell neoplasia characterized by protumor immune dysregulation involving nonmalignant cells of the microenvironment, including T lymphocytes and tumor-associated myeloid cells. Although therapeutic agents have improved treatment options for CLL, many patients still fail to respond. Some patients also show immunosuppression. We have investigated trabectedin, a marine-derived compound with cytotoxic activity on macrophages in solid tumors. Here, we demonstrate that trabectedin induces apoptosis of human primary leukemic cells and also selected myeloid and lymphoid immunosuppressive cells, mainly through the TRAIL/TNF pathway. Trabectedin modulates transcription and translation of IL6, CCL2, and IFNα in myeloid cells and FOXP3 in regulatory T cells. Human memory CD8 T cells downregulate PD-1 and, along with monocytes, exert antitumor function. In xenograft and immunocompetent CLL mouse models, trabectedin has antileukemic effects and antitumor impact on the myeloid and lymphoid cells compartment. It depletes myeloid-derived suppressor cells and tumor-associated macrophages and increases memory T cells. Trabectedin also blocks the PD-1/PD-L1 axis by targeting PD-L1 CLL cells, PD-L1 monocytes/macrophages, and PD-1 T cells. Thus, trabectedin behaves as an immunomodulatory drug with potentially attractive therapeutic value in the subversion of the protumor microenvironment and in overcoming chemoimmune resistance.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891195PMC
December 2019

Exercise or manual physiotherapy compared with a single session of physiotherapy for osteoporotic vertebral fracture: three-arm PROVE RCT.

Health Technol Assess 2019 08;23(44):1-318

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: A total of 25,000 people in the UK have osteoporotic vertebral fracture (OVF). Evidence suggests that physiotherapy may have an important treatment role.

Objective: The objective was to investigate the clinical effectiveness and cost-effectiveness of two different physiotherapy programmes for people with OVF compared with a single physiotherapy session.

Design: This was a prospective, adaptive, multicentre, assessor-blinded randomised controlled trial (RCT) with nested qualitative and health economic studies.

Setting: This trial was based in 21 NHS physiotherapy departments.

Participants: The participants were people with symptomatic OVF.

Interventions: Seven sessions of either manual outpatient physiotherapy or exercise outpatient physiotherapy compared with the best practice of a 1-hour single session of physiotherapy (SSPT).

Main Outcome Measures: Outcomes were measured at 4 and 12 months. The primary outcomes were quality of life and muscle endurance, which were measured by the disease-specific QUALEFFO-41 (Quality of Life Questionnaire of the European Foundation for Osteoporosis - 41 items) and timed loaded standing (TLS) test, respectively. Secondary outcomes were (1) thoracic kyphosis angle, (2) balance, evaluated via the functional reach test (FRT), and (3) physical function, assessed via the Short Physical Performance Battery (SPPB), 6-minute walk test (6MWT), Physical Activity Scale for the Elderly, a health resource use and falls diary, and the EuroQol-5 Dimensions, five-level version.

Results: A total of 615 participants were enrolled, with 216, 203 and 196 randomised by a computer-generated program to exercise therapy, manual therapy and a SSPT, respectively. Baseline data were available for 613 participants, 531 (86.6%) of whom were women; the mean age of these participants was 72.14 years (standard deviation 9.09 years). Primary outcome data were obtained for 69% of participants (429/615) at 12 months: 175 in the exercise therapy arm, 181 in the manual therapy arm and 173 in the SSPT arm. Interim analysis met the criteria for all arms to remain in the study. For the primary outcomes at 12 months, there were no significant benefits over SSPT of exercise [QUALEFFO-41, difference -0.23 points, 95% confidence interval (CI) -3.20 to 1.59 points;  = 1.000; and TLS test, difference 5.77 seconds, 95% CI -4.85 to 20.46 seconds;  = 0.437] or of manual therapy (QUALEFFO-41, difference 1.35 points, 95% CI -1.76 to 2.93 points;  = 0.744; TLS test, difference 9.69 seconds (95% CI 0.09 to 24.86 seconds;  = 0.335). At 4 months, there were significant gains for both manual therapy and exercise therapy over SSPT in the TLS test in participants aged < 70 years. Exercise therapy was superior to a SSPT at 4 months in the SPPB, FRT and 6MWT and manual therapy was superior to a SSPT at 4 months in the TLS test and FRT. Neither manual therapy nor exercise therapy was cost-effective relative to a SSPT using the threshold of £20,000 per quality-adjusted life-year. There were no treatment-related serious adverse events.

Conclusions: This is the largest RCT to date assessing physiotherapy in participants with OVFs. At 1 year, neither treatment intervention conferred more benefit than a single 1-hour physiotherapy advice session. The focus of future work should be on the intensity and duration of interventions to determine if changes to these would demonstrate more sustained effects.

Trial Registration: Current Controlled Trials ISRCTN49117867.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 23, No. 44. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta23440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732718PMC
August 2019

Ibrutinib and Venetoclax for First-Line Treatment of CLL. Reply.

N Engl J Med 2019 08;381(8):789

University of Texas M.D. Anderson Cancer Center, Houston, TX

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http://dx.doi.org/10.1056/NEJMc1908754DOI Listing
August 2019

Induction of apoptosis by MCL-1 inhibitors in chronic lymphocytic leukemia cells.

Leuk Lymphoma 2019 12 4;60(12):3063-3066. Epub 2019 Jun 4.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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http://dx.doi.org/10.1080/10428194.2019.1622098DOI Listing
December 2019

Ibrutinib and Venetoclax for First-Line Treatment of CLL.

N Engl J Med 2019 05;380(22):2095-2103

From the Departments of Leukemia (N.J., M. Keating, P.T., A.F., J.B., G.B., K.T., Z.E., T.K., M. Konopleva, Y.A., M.Y., C.D., P.B., M.O., N.P., E.J., K. Sasaki, K. Sondermann, N.C., C.W., A.A., H.K., W.W.), Lymphoma and Myeloma (N.F.), Hematopathology (R.K.-S., K.P., J.J.), Diagnostic Radiology (N.G.), Biostatistics (X.W.), and Experimental Therapeutics (W.P., V.G.), University of Texas M.D. Anderson Cancer Center, Houston.

Background: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination.

Methods: We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated , chromosome 11q deletion, unmutated , or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10).

Results: A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated , aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax.

Conclusions: In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).
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http://dx.doi.org/10.1056/NEJMoa1900574DOI Listing
May 2019

PIM kinase inhibitor, AZD1208, inhibits protein translation and induces autophagy in primary chronic lymphocytic leukemia cells.

Oncotarget 2019 Apr 19;10(29):2793-2809. Epub 2019 Apr 19.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The PIM1, PIM2, and PIM3 serine/threonine kinases play a role in the proliferation and survival of cancer cells. Mice lacking these three kinases were viable. Further, in human hematological malignancies, these proteins are overexpressed making them suitable targets. Several small molecule inhibitors against this enzyme were synthesized and tested. AZD1208, an orally available small-molecule drug, inhibits all three PIM kinases at a low nanomolar range. AZD1208 has been tested in clinical trials for patients with solid tumors and hematological malignancies, especially acute myelogenous leukemia. The present study evaluated the efficacy and biological actions of AZD1208 in chronic lymphocytic leukemia (CLL) cells. CLL cells had higher levels of PIM2 protein and mRNAs than did normal lymphocytes from healthy donors. Treatment of CLL lymphocytes with AZD1208 resulted in modest cell death, whereas practically no cytotoxicity was observed in healthy lymphocytes. To determine the mechanism by which AZD1208 inhibits PIM kinase function, we evaluated PIM kinase pathway and downstream substrates. Because peripheral blood CLL cells are replicationally quiescent, we analyzed substrates involved in apoptosis, transcription, and translation but not cell cycle targets. AZD1208 inhibited protein translation by decreasing phosphorylation levels of 4E-binding protein 1 (4E-BP1). AZD1208 induced autophagy in replicationally-quiescent CLL cells, which is consistent with protein translation inhibition. These data suggest that AZD1208 may elicit cytotoxicity in CLL cells through inhibiting translation and autophagy induction.
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http://dx.doi.org/10.18632/oncotarget.26876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497463PMC
April 2019

LKB1 and KEAP1/NRF2 Pathways Cooperatively Promote Metabolic Reprogramming with Enhanced Glutamine Dependence in -Mutant Lung Adenocarcinoma.

Cancer Res 2019 07 30;79(13):3251-3267. Epub 2019 Apr 30.

Department of Thoracic, Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

In -mutant lung adenocarcinoma, tumors with LKB1 loss (KL) are highly enriched for concurrent mutations, which activate the KEAP1/NRF2 pathway (KLK). Here, we investigated the biological consequences of these cooccurring alterations and explored whether they conferred specific therapeutic vulnerabilities. Compared with KL tumors, KLK tumors exhibited increased expression of genes involved in glutamine metabolism, the tricarboxylic acid cycle, and the redox homeostasis signature. Using isogenic pairs with knockdown or overexpression of LKB1, KEAP1, and NRF2, we found that LKB1 loss results in increased energetic and redox stress marked by increased levels of intracellular reactive oxygen species and decreased levels of ATP, NADPH/NADP ratio, and glutathione. Activation of the KEAP1/NRF2 axis in LKB1-deficient cells enhanced cell survival and played a critical role in the maintenance of energetic and redox homeostasis in a glutamine-dependent manner. LKB1 and the KEAP1/NRF2 pathways cooperatively drove metabolic reprogramming and enhanced sensitivity to the glutaminase inhibitor CB-839 and . Overall, these findings elucidate the adaptive advantage provided by KEAP1/NRF2 pathway activation in KL tumors and support clinical testing of glutaminase inhibitor in subsets of KRAS-mutant lung adenocarcinoma. SIGNIFICANCE: In -mutant non-small cell lung cancer, LKB1 loss results in enhanced energetic/redox stress, which is tolerated, in part, through cooccurring KEAP1/NRF2-dependent metabolic adaptations, thus enhancing glutamine dependence and vulnerability to glutaminase inhibition. http://cancerres.aacrjournals.org/content/canres/79/13/3251/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606351PMC
July 2019

8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia.

J Cell Physiol 2019 Feb 15. Epub 2019 Feb 15.

Hematology Malignancies and Stem Cell Transplantation Institute, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, California.

Nucleoside analogs represent the backbone of several distinct chemotherapy regimens for acute myeloid leukemia (AML) and combination with tyrosine kinase inhibitors has improved survival of AML patients, including those harboring the poor-risk FLT3-ITD mutation. Although these compounds are effective in killing proliferating blasts, they lack activity against quiescent leukemia stem cells (LSCs), which contributes to initial treatment refractoriness or subsequent disease relapse. The reagent 8-chloro-adenosine (8-Cl-Ado) is a ribose-containing, RNA-directed nucleoside analog that is incorporated into newly transcribed RNA rather than in DNA, causing inhibition of RNA transcription. In this report, we demonstrate antileukemic activities of 8-Cl-Ado in vitro and in vivo and provide mechanistic insight into the mode of action of 8-Cl-Ado in AML. 8-Cl-Ado markedly induced apoptosis in LSC, with negligible effects on normal stem cells. 8-Cl-Ado was particularly effective against AML cell lines and primary AML blast cells harboring the FLT3-ITD mutation. FLT3-ITD is associated with high expression of miR-155. Furthermore, we demonstrate that 8-Cl-Ado inhibits miR-155 expression levels accompanied by induction of DNA-damage and suppression of cell proliferation, through regulation of miR-155/ErbB3 binding protein 1(Ebp1)/p53/PCNA signaling. Finally, we determined that combined treatment of NSG mice engrafted with FLT3-ITD MV4-11 AML cells with 8-Cl-Ado and the FLT3 inhibitor AC220 (quizartinib) synergistically enhanced survival, compared with that of mice treated with the individual drugs, suggesting a potentially effective approach for FLT3-ITD AML patients.
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http://dx.doi.org/10.1002/jcp.28294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697246PMC
February 2019

Ibrutinib dose and clinical outcome in chronic lymphocytic leukemia - learning from the 'real world'.

Leuk Lymphoma 2019 07 6;60(7):1603-1605. Epub 2019 Feb 6.

a Department of Leukemia , MD Anderson Cancer Center , Houston , TX , USA.

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http://dx.doi.org/10.1080/10428194.2019.1571207DOI Listing
July 2019

Extracellular Flux Assays to Determine Oxidative Phosphorylation and Glycolysis in Chronic Lymphocytic Leukemia Cells.

Methods Mol Biol 2019 ;1881:121-128

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Extracellular flux assays are conducted using seahorse XF96 analyzer. They are used to calculate oxygen consumption rate which is to determine mitochondrial oxidative phosphorylation and extracellular acidification rate which is a measure of glycolysis. Collectively, these assays are used to assess the metabolic phenotype of a cell. Up to four drugs can be loaded and tested in the XF cartridges used in the assay and their effect on cells could be determined. While adherent cell lines are easy to use for this assay, suspension cultures or primary cells are difficult to use. In the following sections, we describe the methodology for this assay for CLL cells in suspension cultures and CLL-stroma cocultures.
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http://dx.doi.org/10.1007/978-1-4939-8876-1_10DOI Listing
June 2019

In Vitro Assay to Study CLL and Monocyte Interactions.

Methods Mol Biol 2019 ;1881:113-119

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Investigations focusing on CLL and microenvironment interaction allow understanding role of each component of the microenvironment. In vitro cell depletion assay we described here enables us to evaluate the depletion of CLL cells and monocyte populations upon treatment with drugs targeting the interactions between CLL cells and monocytes. The assay is based on a quantitative multi-color flow cytometry analysis and, when combined to fluorescence-activated cell sorting and RT-PCR, it allows the isolation of CLL/monocyte cells and the further characterization of apoptotic and/or inflammatory pathways induced eventually on CLL cells and on monocytes.
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http://dx.doi.org/10.1007/978-1-4939-8876-1_9DOI Listing
June 2019

Ex Vivo Pharmacological Profiling in Chronic Lymphocytic Leukemia Cells.

Methods Mol Biol 2019 ;1881:19-25

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

In vitro drug combination studies are commonly used for CLL primary lymphocytes. An advancement in this method is to perform ex vivo drug testing where the first agent is administered to patients and second drug is tested in these patients' cells in vitro. These assays have been effective in identifying novel agents that work additively or synergistically. In this chapter, we provide a step-by-step protocol for ex vivo drug testing that can be used for combination strategies.
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http://dx.doi.org/10.1007/978-1-4939-8876-1_2DOI Listing
June 2019

Better Outcomes for Older people with Spinal Trouble (BOOST) Trial: a randomised controlled trial of a combined physical and psychological intervention for older adults with neurogenic claudication, a protocol.

BMJ Open 2018 10 18;8(10):e022205. Epub 2018 Oct 18.

Centre for Rehabilitation Research, Nuffield Department of Rhuematology, Orthopaedics and Musculskeletal Sciences, University of Oxford, Oxford, UK.

Introduction: Neurogenic claudication due to spinal stenosis is common in older adults. The effectiveness of conservative interventions is not known. The aim of the study is to estimate the clinical and cost-effectiveness of a physiotherapist-delivered, combined physical and psychological intervention.

Methods And Analysis: This is a pragmatic, multicentred, randomised controlled trial. Participants are randomised to a combined physical and psychological intervention (Better Outcomes for Older people with Spinal Trouble (BOOST) programme) or best practice advice (control). Community-dwelling adults, 65 years and over, with neurogenic claudication are identified from community and secondary care services. Recruitment is supplemented using a primary care-based cohort. Participants are registered prospectively and randomised in a 2:1 ratio (intervention:control) using a web-based service to ensure allocation concealment. The target sample size is a minimum of 402. The BOOST programme consists of an individual assessment and twelve 90 min classes, including education and discussion underpinned by cognitive behavioural techniques, exercises and walking circuit. During and after the classes, participants undertake home exercises and there are two support telephone calls to promote adherence with the exercises. Best practice advice is delivered in one to three individual sessions with a physiotherapist. The primary outcome is the Oswestry Disability Index at 12 months. Secondary outcomes include the 6 Minute Walk Test, Short Physical Performance Battery, Fear Avoidance Beliefs Questionnaire and Gait Self-Efficacy Scale. Outcomes are measured at 6 and 12 months by researchers who are masked to treatment allocation. The primary statistical analysis will be by 'intention to treat'. There is a parallel health economic evaluation and qualitative study.

Ethics And Dissemination: Ethical approval was given on 3 March 2016 (National Research Ethics Committee number: 16/LO/0349). This protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials checklist. The results will be reported at conferences and in peer-reviewed publications using the Consolidated Standards of Reporting Trials guidelines. A plain English summary will be published on the BOOST website.

Trial Registration Number: ISRCTN12698674; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-022205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196848PMC
October 2018

A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia.

Blood 2018 11 25;132(21):2249-2259. Epub 2018 Sep 25.

Department of Experimental Therapeutics.

Ibrutinib is highly efficacious and used at 420 mg/d for treatment of chronic lymphocytic leukemia (CLL). We previously demonstrated a decline in Bruton's tyrosine kinase (BTK) protein levels in CLL cells after 1 cycle of ibrutinib, suggesting ibrutinib dose could be lowered after the first cycle without loss of biological effect. To test this postulate, a pilot study (NCT02801578) was designed to systematically reduce ibrutinib dosing within the same patient with CLL over the course of three 28-day cycles. After an initial cycle of 420 mg/d, the dose was reduced to 280 mg/d in cycle 2, and then to 140 mg/d in cycle 3. Eleven patients began study treatment, and 9 completed the 3 cycles. Plasma and intracellular pharmacokinetics (PK), BTK occupancy, and pharmacodynamic (PD) response at different doses of ibrutinib were compared. Plasma and intracellular levels of ibrutinib were dose-dependent, and even the lowest dose was sufficient to occupy, on average, more than 95% of BTK protein. In concert, BTK downstream signaling inhibition was maintained with 140 mg/d ibrutinib in cycle 3, and there were comparable reductions in total and phospho-BTK (Tyr223) protein levels across 3 cycles. Reductions of plasma chemokine CCL3 and CCL4 levels, considered to be biomarkers of ibrutinib response, were similar during the 3 cycles. These PK/PD data demonstrate that after 1 cycle of ibrutinib at the standard 420 mg/d dose, the dose can be reduced without losing biological activity. Clinical efficacy of lower doses needs to be systematically evaluated. Such dose reductions would lower drug cost, lessen untoward toxicity, and facilitate rationale-based combinations. This trial was registered at www.clinicaltrials.gov as #NCT02801578.
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http://dx.doi.org/10.1182/blood-2018-06-860593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251009PMC
November 2018

Discovery and Optimization of Novel Hydrogen Peroxide Activated Aromatic Nitrogen Mustard Derivatives as Highly Potent Anticancer Agents.

J Med Chem 2018 10 10;61(20):9132-9145. Epub 2018 Oct 10.

Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery , University of Wisconsin, Milwaukee , 3210 North Cramer Street , Milwaukee , Wisconsin 53211 , United States.

We describe several new aromatic nitrogen mustards with various aromatic substituents and boronic esters that can be activated with HO to efficiently cross-link DNA. In vitro studies demonstrated the anticancer potential of these compounds at lower concentrations than those of other clinically used chemotherapeutics, such as melphalan and chlorambucil. In particular, compound 10, bearing an amino acid ester chain, is selectively cytotoxic toward breast cancer and leukemia cells that have inherently high levels of reactive oxygen species. Importantly, 10 was 10-14-fold more efficacious than melphalan and chlorambucil for triple-negative breast-cancer (TNBC) cells. Similarly, 10 is more toxic toward primary chronic-lymphocytic-leukemia cells than either chlorambucil or the lead compound, 9. The introduction of an amino acid side chain improved the solubility and permeability of 10. Furthermore, 10 inhibited the growth of TNBC tumors in xenografted mice without obvious signs of general toxicity, making this compound an ideal drug candidate for clinical development.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00559DOI Listing
October 2018

What evidence is used to underpin the design of strength-based exercise interventions evaluated in randomised controlled trials for rheumatoid arthritis? A systematic review protocol.

BMJ Open 2018 09 10;8(9):e024127. Epub 2018 Sep 10.

Department of Clinical Sciences, Institute of Environment, Health and Societies, Brunel University London, Uxbridge, UK.

Introduction: Healthcare researchers designing strength-based exercise interventions must choose an appropriate dose to test before evaluating its effect using a definitive/phase-III randomised controlled trial (RCT). Compared with early phase testing employed by pharmaceutical trials, it is questionable whether exercise-based trials employ the same rigour for establishing tolerated dosage. Consequently, it is unclear if participants are initially prescribed optimal doses of exercise, which may potentially impact on study outcomes. Using trials of strength-based exercise interventions in adults with rheumatoid arthritis (RA) as an exemplar, the aims of this review are to (1) identify the proportion of RCTs that use phase I/II trials with dose escalation methodology for setting prescription parameters, (2) determine type and level of evidence used to justify prescription parameters of strength-based exercise interventions evaluated by RCTs, (3) explore consistency and applicability of the evidence underpinning prescription parameters in RCTs and (4) explore if a relationship exists between risk of bias for RCTs evaluating strength-based interventions and the level of evidence used to underpin prescription parameters.

Methods And Analysis: Focusing on RCT's evaluating strength-based exercise interventions in adults with RA published after 2000, the following databases will be searched: Allied and Complementary Medicine Database, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Excerpta Medica Database, Medline and Physiotherapy Evidence Database. For each RCT, we will identify the evidence used to underpin prescription parameters. Both trial and underpinning evidence will have key information about the intervention extracted using the template for intervention description and replication checklist. Risk of bias will be assessed according to Cochrane. Levels of evidence will be assessed against the Oxford Centre for Evidence-Based Medicine and relationships between RCT and underpinning evidence explored and described narratively. Two independent assessors will be involved throughout data selection and extraction with recourse to a third reviewer should agreement not be reached.

Ethics And Dissemination: No ethical issues are identified. Dissemination will be via publication.

Prospero Registration Number: CRD42018090963.
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http://dx.doi.org/10.1136/bmjopen-2018-024127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144333PMC
September 2018

Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients.

Pharmacogenomics 2018 09 8;19(14):1101-1110. Epub 2018 Aug 8.

Department of Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.

Aim: Cytarabine (Ara-C), a mainstay of acute myeloid leukemia (AML) treatment, is a prodrug requiring activation to ara-CTP for its antileukemic activity. Aim of this study was to evaluate impact of genetic variants in the key genes involved in ara-C metabolism on the leukemic cell intracellular levels of ara-CTP.

Method: We investigated SNPs in 14 ara-C metabolic-pathway genes, for association with intracellular ara-CTP levels, in leukemic cells obtained post-initiation of cytarabine infusion in pediatric AML patients (n = 68).

Results: Nine SNPs were significantly associated with leukemic cell intracellular concentration of ara-CTP. A comprehensive ara-CTP-SNP-score (ACSS) was further developed from top four SNPs identified in regression model. Patients were classified into three groups based on ACSS: high-ACSS (score >0), intermediate-ACSS (score = 0) and low-ACSS (score <0). ACSS designation was significant predictor of intracellular ara-CTP levels (p = 0.00012), suggesting a cumulative or synergistic effect of the significant SNPs.

Conclusion: ACSS score designation holds promise in definfing ara-C dose. Validation of the clinical utility of ACSS score in other independent cohorts will help identification of patients with potentially lower or higher levels of the ara-CTP in leukemic cells, thereby opening up opportunities for dose management to reduce toxicity and enhance efficacy.
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http://dx.doi.org/10.2217/pgs-2018-0086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219441PMC
September 2018

A Pilot Phase II Study of Erlotinib for the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia.

Acta Haematol 2018 2;140(1):30-39. Epub 2018 Aug 2.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, may have off-target activity inducing acute myeloid leukemia (AML) differentiation, possibly through SYK inhibition. We investigated erlotinib in a pilot phase II study for efficacy in relapsed/refractory AML patients at a dose of 150 mg once daily in 28-day cycles. Twenty-nine patients were treated for a median of 29 days (range 12-142 days). Seven patients (24%) received > 1 cycle of therapy and 12 (41%) discontinued treatment before day 28 due to disease progression. One patient (3%) achieved complete remission and 2 (7%) a > 50% reduction in blasts. The most common toxicities associated with erlotinib were fatigue in 10 patients (34%), diarrhea in 10 (34%), nausea in 8 (28%), and rash in 7 (24%). Only 2 patients (7%) had study drug-related adverse events requiring dose reductions and eventual discontinuation. The main reason for treatment discontinuation was disease progression in 26 patients (90%). All patients had died by the time of the last follow-up. Progression of disease was the primary cause of death in all patients. Median overall survival was 14 weeks (range 2.3-96.9 weeks) and median event-free survival was 5 weeks (range 1.7-21.0 weeks). Erlotinib as a single agent has limited clinical efficacy in patients with relapsed/refractory AML.
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http://dx.doi.org/10.1159/000490092DOI Listing
June 2019

Biological and metabolic effects of IACS-010759, an OxPhos inhibitor, on chronic lymphocytic leukemia cells.

Oncotarget 2018 May 18;9(38):24980-24991. Epub 2018 May 18.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Blood cells from patients with chronic lymphocytic leukemia (CLL) are replicationally quiescent but transcriptionally, translationally, and metabolically active. Recently, we demonstrated that oxidative phosphorylation (OxPhos) is a predominant pathway in CLL for energy production and is further augmented in the presence of the stromal microenvironment. Importantly, CLL cells from patients with poor prognostic markers showed increased OxPhos. From these data, we theorized that OxPhos can be targeted to treat CLL. IACS-010759, currently in clinical development, is a small-molecule, orally bioavailable OxPhos inhibitor that targets mitochondrial complex I. Treatment of primary CLL cells with IACS-010759 greatly inhibited OxPhos but caused only minor cell death at 24 and 48 h. In the presence of stroma, the drug successfully inhibited OxPhos and diminished intracellular ribonucleotide pools. However, glycolysis and glucose uptake were induced as compensatory mechanisms. To mitigate the upregulated glycolytic flux, we used 2-deoxy-D-glucose in combination with IACS-010759. This combination reduced both OxPhos and glycolysis and induced cell death. Consistent with these data, low-glucose culture conditions sensitized CLL cells to IACS-010759. Collectively, these data suggest that CLL cells adapt to use a different metabolic pathway when OxPhos is inhibited and that targeting both OxPhos and glycolysis pathways is necessary for biological effect.
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http://dx.doi.org/10.18632/oncotarget.25166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982765PMC
May 2018

Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers.

Br J Cancer 2018 05 16;118(11):1425-1433. Epub 2018 May 16.

Clinical Trials Unit, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK.

Background: Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours.

Methods: Two dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208.

Results: Sixty-seven patients received treatment: 32 in the AML study over a 120-900 mg dose range, and 25 in the solid tumour study over a 120-800 mg dose range. Nearly all patients (98.5%) in both studies experienced adverse events, mostly gastrointestinal (92.5%). Dose-limiting toxicities included rash, fatigue and vomiting. AZD1208 was not tolerated at 900 mg, and the protocol-defined MTD was not confirmed. AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance. There were no clinical responses; PD analysis showed biological activity of AZD1208.

Conclusions: Despite the lack of single-agent clinical efficacy with AZD1208, PIM kinase inhibition may hold potential as an anticancer treatment, perhaps in combination with other agents.
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http://dx.doi.org/10.1038/s41416-018-0082-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988656PMC
May 2018

Recent therapeutic advances in chronic lymphocytic leukemia.

F1000Res 2017 31;6:1924. Epub 2017 Oct 31.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The last several years have witnessed a paradigm shift in the management of patients with chronic lymphocytic leukemia (CLL). The course of this very heterogeneous disease, traditionally treated with chemotherapeutic agents usually in combination with rituximab, typically has been characterized by remissions and relapses, and survival times vary greatly, depending on intrinsic biological attributes of the leukemia. The developments of the last few years have been transformative, ushering in an era of novel, molecularly targeted therapies, made possible by extensive efforts to elucidate the biology of the disease that predated the new targeted drugs. Thus, successful therapeutic targeting of the B-cell receptor signaling pathway and of the Bcl-2 anti-apoptotic protein with small molecules has now made chemotherapy-free approaches possible, hopefully mitigating the risk of development of therapy-related myeloid neoplasms and making eventual cure of CLL with the use of optimal drug combinations a realistic goal. Most importantly, these therapies have demonstrated unprecedented efficacy in patients with deletion 17p/TP53 mutation, a subset that historically has been very difficult to treat. However, as we gain more experience with the newer agents, unique safety concerns and resistance mechanisms have emerged, as has the issue of cost, as these expensive drugs are currently administered indefinitely. Accordingly, novel laboratory-based strategies and clinical trial designs are being explored to address these issues. The availability of whole exome/genome sequencing has given us profound insights into the mutational landscape of CLL. In this article, we highlight some of the most impactful advances since this topic was last reviewed in this journal.
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http://dx.doi.org/10.12688/f1000research.11618.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664994PMC
October 2017

Proteomics profiling identifies induction of caveolin-1 in chronic lymphocytic leukemia cells by bone marrow stromal cells.

Leuk Lymphoma 2018 06 3;59(6):1427-1438. Epub 2017 Oct 3.

a Department of Experimental Therapeutics , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.

Chronic lymphocytic leukemia (CLL) is an indolent B-cell malignancy in which cells reside in bone marrow, lymph nodes, and peripheral blood, each of which provides a unique microenvironment. Although the levels of certain proteins are reported to induce, changes in the CLL cell proteome in the presence of bone marrow stromal cells have not been elucidated. Reverse-phase protein array analysis of CLL cells before and 24 h after stromal cell interaction revealed changed levels of proteins that regulate cell cycle, gene transcription, and protein translation. The most hit with respect to both the extent of change in expression level and statistical significance was caveolin-1, which was confirmed with immunoblotting. Caveolin-1 mRNA levels were also upregulated in CLL cells after stromal cell interaction. The induction of caveolin-1 levels was rapid and occurred as early as 1 h. Studies to determine the significance of upregulated caveolin-1 levels in CLL lymphocytes are warranted.
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http://dx.doi.org/10.1080/10428194.2017.1376747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882591PMC
June 2018