Maciej Kmieciak - Academia.edu (original) (raw)

Papers by Maciej Kmieciak

Cancer Research, 2018

Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acu... more Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those beari...

The caspase inhibitor BOC-D-fmk does not change HHT/Bort–mediated down-regulation of MCL-1. OCI-L... more The caspase inhibitor BOC-D-fmk does not change HHT/Bort–mediated down-regulation of MCL-1. OCI-LY18 and Carnaval cells were treated with HHT + Bort for 24 h either in the absence or presence of 5 μmol/L BOC-D-fmk. At the end of this period, cells were lysed and subjected to Western blot analysis using the indicated primary antibodies. Each lane was loaded with 25 μg of protein. Blots were stripped and reprobed with antitubulin antibodies to ensure equal loading and transfer of protein. Representative of two separate experiments. (PPTX 100 kb)

HHT inhibits MCL-1 expression through a post-transcriptional mechanism. A. SU-DHL4 and SU-DHL16 c... more HHT inhibits MCL-1 expression through a post-transcriptional mechanism. A. SU-DHL4 and SU-DHL16 cells were treated with HHT for 8 h after which cells were lysed and proteins extracted. Expression of the indicated proteins was determined by Western blotting using the indicated antibodies. B. SU-DHL4 and SU-DHL16 cells were treated with HHT for 8 h after which cells were extracted for mRNA. Relative levels of MCL-1 mRNA/GAPDH were calculated. C. SU-DHL4 and SU-DHL16 cells were pre-treated with actinomycin (2.5 μg/ml) for 30 min and then exposed to HHT 2 h (SU-DHL4 60 nM, SU-DHL16 20 nM) after which cells were lysed and proteins extracted. Expression of the indicated proteins was determined by western blott using the indicated antibodies. D. SU-DHL4 and SU-DHL16 cells were pre-treated with cyclohexamide (5 μg/ml) for 30 min and then exposed to HHT 2 h and 4 h (SU-DHL4 60 nM, SU-DHL16 20 nM) after which cells were lysed and proteins extracted. Expression of the indicated proteins was de...

Table S1. Analogous studies were performed on 43 primary MM samples. (XLSX 11 kb)

A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid l... more A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring

Blood Advances, 2021

Interactions between the inhibitor of apoptosis protein antagonist LCL161 and the histone deacety... more Interactions between the inhibitor of apoptosis protein antagonist LCL161 and the histone deacetylase inhibitor panobinostat (LBH589) were examined in human multiple myeloma (MM) cells. LCL161 and panobinostat interacted synergistically to induce apoptosis in diverse MM cell lines, including those resistant to bortezomib (PS-R). Similar interactions were observed with other histone deacetylase inhibitors (MS-275) or inhibitors of apoptosis protein antagonists (birinapant). These events were associated with downregulation of the noncanonical (but not the canonical) NF-κB pathway and activation of the extrinsic, caspase-8–related apoptotic cascade. Coexposure of MM cells to LCL161/LBH589 induced TRAF3 upregulation and led to TRAF2 and NIK downregulation, diminished expression of BCL-XL, and induction of γH2A.X. Ectopic expression of TRAF2, NIK, or BCL-XL, or short hairpin RNA TRAF3 knock-down, significantly reduced LCL161/LBH589 lethality, as did ectopic expression of dominant-negativ...

Blood, 2011

2926 Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell tr... more 2926 Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Maintenance therapy may delay recurrence but is associated with toxicities, highlighting the need for alternative strategies for long-term disease control. Malignant plasma cells in MM patients occasionally express highly immunogenic cancer testis antigens (CTA). CTA expression is regulated by DNA methylation, and may be increased by 5-azacitidine (Celgene corp., Summit, NJ) (Aza), a DNA hypomethylating agent. The addition of lenalidomide (Celgene corp.) (L) may augment any ensuing adoptive CTA-specific immune response. These immune effector cells may then be collected and adoptively transferred in a setting of lympho-depletion and minimal residual disease following SCT, serving a maintenance function. To demonstrate the feasibility of this approach, we initiated a phase II clinical trial of Aza administered sequentially with L ...

Blood, 2013

Histone deacetylase (e.g., vorinostat) and proteasome inhibitors interact synergistically to prom... more Histone deacetylase (e.g., vorinostat) and proteasome inhibitors interact synergistically to promote cell death in various cancer cells, including malignant human hematopoietic cells. The novel, proteasome inhibitor carfilzomib is an attractive candidate for combination regimens due to diminished neurotoxicity, irreversible proteasome inhibition, favorable tolerability profile relative to bortezomib, and preclinical and clinical evidence of activity in bortezomib-resistant cells and patients. Preclinical studies demonstrated synergistic interactions between carfilzomib and vorinostat in human diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells both in vitro and in vivo as well as in bortezomib-resistant cells (Dasmahapatra et al., Blood 115:4478; 2010; Mol Cancer Ther 10:1686, 2001). These preclinical findings prompted a phase 1 trial, using a 3+3 design, with the goal of determining the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for the comb...

Blood, 2012

3588 Although reports of synergistic interactions between proteasome and histone deacetylase (HDA... more 3588 Although reports of synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in acute leukemias have been limited, they are well described in B-cell malignancies (e.g., myeloma and lymphoma). Nevertheless, preclinical findings have shown striking synergism between the HDAC inhibitor belinostat (previously PXD-101) and the proteasome inhibitor bortezomib, administered at low (sub-micromolar) concentrations, in cultured and primary acute myeloid leukemia (AML) and acute lymphocytic leukemia cells (Dai Y et al. Br J Haematol. 2011). These findings prompted initiation of a phase I trial, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blast crisis (CML-BC). To date, 25 patients with the following disease types have been treated: acute leu...

Cardio-Oncology, 2018

Background: Doxorubicin chemotherapy is used across a range of adult and pediatric malignancies. ... more Background: Doxorubicin chemotherapy is used across a range of adult and pediatric malignancies. Cardiac toxicity is common, and dysfunction develops over time in many patients. Biomarkers used for predicting late cardiac dysfunction following doxorubicin exposure have shown promise. Preclinical studies have demonstrated potential cardioprotective effects of sildenafil. Methods: We sought to confirm the safety of adding sildenafil to doxorubicin-based chemotherapy and assess Nterminal Pro-Brain Natriuretic Peptide (NT-proBNP) and high sensitivity cardiac troponin I (hsTnI) as early markers of anthracycline-induced cardiotoxicity. We randomized 27 patients (ages 31-77, 92.3% female) receiving doxorubicin chemotherapy using a blocked randomization scheme with randomly permuted block sizes to receive standard chemotherapy alone or with the addition of sildenafil. The study was not blinded. Sildenafil was dosed at 100 mg by mouth daily during therapy; patients took sildenafil three times daily on the day of doxorubicin. Doxorubicin dosing and schedule were dependent on the treatment regimen. Echocardiography was obtained prior to initiation of treatment and routinely thereafter up to 4 years. NT-proBNP and hsTnI were obtained with each cycle before, 1-3 h after, and 24 h after doxorubicin. Results: Fourteen patients were randomized to receive standard doxorubicin chemotherapy alone (14 treated and analyzed), while 13 patients were randomized to the experimental doxorubicin and sildenafil arm (10 treated and analyzed). No toxicity signal was seen with the addition of sildenafil to doxorubicin-based regimens. There was no statistical difference between the treatment arms in relation to the change of mean left ventricular ejection fraction (LVEF) between the first and last evaluation. In both arms, hsTnI levels increased over time; however, elevated hsTnI was not associated with declines in LVEF. Conclusion: Adding sildenafil was safe, but did not offer cardioprotection following doxorubicin treatment. Increases in hsTnI levels were observed over time, but elevations during therapy did not correlate with subsequent decreases in LVEF. Trial registration: This clinical trial (NCT01375699) was registered at www.clinicaltrials.gov on June 17, 2011.

Cancer Research, 2016

Inhibitor of apoptosis proteins (IAPs e.g., XIAP, cIAP1, cIAP2) inhibit apoptosis through diverse... more Inhibitor of apoptosis proteins (IAPs e.g., XIAP, cIAP1, cIAP2) inhibit apoptosis through diverse mechanisms. Recent attention has focused on novel functions of cIAP1/2, including activation of the canonical and non-canonical NF-κB pathways and inhibition of the extrinsic apoptotic pathway through the ripoptosome. These considerations have stimulated the development of IAP antagonists such as the bivalent IAP inhibitor birinapant (TL-32711). Proteasome inhibitors such as bortezomib are highly active in multiple myeloma (MM), and act, at least in part, by inhibiting NF-κB, raising the possibility of cooperative interactions with IAP antagonists. Synergistic induction of apoptosis was observed in human MM cell lines, including drug-naïve U266 cells, their bortezomib-resistant counterparts (PS-R), and multiple other human MM lines. Birinapant (500 nM) sharply down-regulated cIAP1/2 in MM cells, accompanied by reduced expression of TRAF2, RIP1, and p-IKKβ, as well as robust TRAF3 up-reg...

Blood, 2011

2931 AZD6244 is a potent, selective, oral, non-ATP competitive small molecule inhibitor of the mi... more 2931 AZD6244 is a potent, selective, oral, non-ATP competitive small molecule inhibitor of the mitogen-activated protein kinase, MEK 1/2 that has shown significant pre-clinical activity in multiple myeloma (MM) cells, both in vitro and in vivo, as well as a favorable clinical profile. The present phase II study was designed to determine the response rate for AZD6244 in patients with relapsed or refractory MM. The study utilized a two-stage Simon design to allow for early termination if there was strong evidence of regimen inactivity. Eligible patients were restricted to those with MM who have had at least 2 prior regimens. AZD6244 capsules (75 mg) were administered orally twice daily continuously for 28 day cycles. Response was evaluated after 3 cycles. To date, 37 patients have been enrolled (13 in the 1st stage and 24 in the 2nd stage). One subject enrolled in the 1st stage was not treated. Gender enrollment was balanced (male/female 18/19). The median age of treated patients was ...

Leukemia & Lymphoma, 2020

We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult pa... more We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1000 mg/m2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation.

Blood, 2012

1794 Preclinical studies have demonstrated synergistic interactions between proteasome and histon... more 1794 Preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in diverse hematologic malignancies, including those of B-cell origin. We have previously shown that the combination of the proteasome inhibitor bortezomib and the HDAC inhibitor romidepsin, administered at extremely low concentrations (∼3–5 nM), results in a striking increase in apoptosis in primary CLL cells, including cells from patients with CLL refractory to standard treatments (Dai Y et al. Clin Cancer Res. 2008). These findings prompted initiation of a phase I trial, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and romidepsin in patients with relapsed or refractory chronic lymphocyte leukemia/small lymphocytic lymphoma (CLL/SLL), indolent B-cell lymphoma, or peripheral T-cell lymphoma (PTCL). To date, 11 patients have been enrolled and treated. All of the patients tr...

Clinical Cancer Research, 2013

Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocid... more Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination. Experimental Design: Patients received vorinostat (200 mg orally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily × 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly × 2. The alvocidib dose was escalated using a standard 3+3 design. Results: Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m2 (30-minute loading infusion) followed by 20 mg/m2 (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities we...

British Journal of Haematology, 2012

Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transpl... more Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens (CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine (Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza-Rev and cryopreserved. Subsequent stem cell mobilization was followed by high-dose melphalan and SCT. Autologous lymphocyte infusion (ALI) was performed in the second month following transplantation. Fourteen patients have

Biology of Blood and Marrow Transplantation, 2011

to support one over the others. We historically used CSA/MTX (n 5 187 pts). Over the last 3 years... more to support one over the others. We historically used CSA/MTX (n 5 187 pts). Over the last 3 years we used CSA/MMF (n 5 92). Median pt age was 52 years (18-73). Diagnoses included AML/MDS (n 5 152), ALL (n 5 30), CML (n 5 12), myeloma (n 5 24), lymphoma (n 5 40), others (n 5 21). The donor was 10/10 (n 5 191), 9/10 (n 5 54) or # 8/ 10 match (n 5 34). Conditioning was myeloablative (n 5 58) or reduced intensity/toxicity (RIC, n 5 221). Non-relapse mortality (NRM) is dependant on regimen toxicity and GVHD. CSA/MMF was less toxic than CSA/MTX. It allowed faster engraftment, day +11 and +14, respectively (p \ 0.001). Day30 mortality was 2.2% and 10.7%, respectively (p 5 0.04). Multivariate analysis (MVA) identified high comorbidity index (HR 2.5, p 5 0.05), advanced disease (HR 6.2, p 5 0.005), mismatched donor (HR 2.4, p 5 0.03) and lymphoid malignancies (HR 2.8, p 5 0.03) as adverse factors for regimen-related mortality. CSA/MMF was protective (HR 0.4, p 5 0.02). However, CSA/MMF was less effective in preventing grade III-IV acute GVHD; cumulative incidence 29% and 18%, respectively (p 5 0.005). MVA identified mismatched donor (HR 3.4, p 5 0.001) and CSA/MMF (HR 2.4, p 5 0.004) as adverse factors, while RIC was protective (HR 0.4, p 5 0.01). The net effect was that NRM was equivalent with both regimens. GVHD regimen had major impact on overall survival (OS) when pts were stratified based on disease status. In early stage disease, OS was 65% and 42%, after CSA/MTX and CSA/MMF, respectively (HR 1.9, p 5 0.05), predominantly due to excess GVHD deaths in the MMF group. In advanced disease, OS was better with CSA/MMF; 20% and 12%, respectively (HR 0.5, p 5 0.04), predominantly due to less relapses. In conclusion, GVHD prevention regimen has major impact on outcome after MUD SCT. CSA/MMF is a less toxic regimen and allows prompt engraftment, but is less effective in preventing GVHD. In early stage disease, outcome is dominated by NRM and more effective GVHD prevention regimen such as CSA/MTX is needed. In advanced disease both toxicity and relapse increase. A less intensive regimen, that also better preserves GVL, such as CSA/MMF, may be associated with better outcome. The GVHD prevention regimen selected may need to be tailored to pt and disease characteristics.

Cancer Research, 2018

Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acu... more Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those beari...

The caspase inhibitor BOC-D-fmk does not change HHT/Bort–mediated down-regulation of MCL-1. OCI-L... more The caspase inhibitor BOC-D-fmk does not change HHT/Bort–mediated down-regulation of MCL-1. OCI-LY18 and Carnaval cells were treated with HHT + Bort for 24 h either in the absence or presence of 5 μmol/L BOC-D-fmk. At the end of this period, cells were lysed and subjected to Western blot analysis using the indicated primary antibodies. Each lane was loaded with 25 μg of protein. Blots were stripped and reprobed with antitubulin antibodies to ensure equal loading and transfer of protein. Representative of two separate experiments. (PPTX 100 kb)

HHT inhibits MCL-1 expression through a post-transcriptional mechanism. A. SU-DHL4 and SU-DHL16 c... more HHT inhibits MCL-1 expression through a post-transcriptional mechanism. A. SU-DHL4 and SU-DHL16 cells were treated with HHT for 8 h after which cells were lysed and proteins extracted. Expression of the indicated proteins was determined by Western blotting using the indicated antibodies. B. SU-DHL4 and SU-DHL16 cells were treated with HHT for 8 h after which cells were extracted for mRNA. Relative levels of MCL-1 mRNA/GAPDH were calculated. C. SU-DHL4 and SU-DHL16 cells were pre-treated with actinomycin (2.5 μg/ml) for 30 min and then exposed to HHT 2 h (SU-DHL4 60 nM, SU-DHL16 20 nM) after which cells were lysed and proteins extracted. Expression of the indicated proteins was determined by western blott using the indicated antibodies. D. SU-DHL4 and SU-DHL16 cells were pre-treated with cyclohexamide (5 μg/ml) for 30 min and then exposed to HHT 2 h and 4 h (SU-DHL4 60 nM, SU-DHL16 20 nM) after which cells were lysed and proteins extracted. Expression of the indicated proteins was de...

Table S1. Analogous studies were performed on 43 primary MM samples. (XLSX 11 kb)

A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid l... more A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring

Blood Advances, 2021

Interactions between the inhibitor of apoptosis protein antagonist LCL161 and the histone deacety... more Interactions between the inhibitor of apoptosis protein antagonist LCL161 and the histone deacetylase inhibitor panobinostat (LBH589) were examined in human multiple myeloma (MM) cells. LCL161 and panobinostat interacted synergistically to induce apoptosis in diverse MM cell lines, including those resistant to bortezomib (PS-R). Similar interactions were observed with other histone deacetylase inhibitors (MS-275) or inhibitors of apoptosis protein antagonists (birinapant). These events were associated with downregulation of the noncanonical (but not the canonical) NF-κB pathway and activation of the extrinsic, caspase-8–related apoptotic cascade. Coexposure of MM cells to LCL161/LBH589 induced TRAF3 upregulation and led to TRAF2 and NIK downregulation, diminished expression of BCL-XL, and induction of γH2A.X. Ectopic expression of TRAF2, NIK, or BCL-XL, or short hairpin RNA TRAF3 knock-down, significantly reduced LCL161/LBH589 lethality, as did ectopic expression of dominant-negativ...

Blood, 2011

2926 Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell tr... more 2926 Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Maintenance therapy may delay recurrence but is associated with toxicities, highlighting the need for alternative strategies for long-term disease control. Malignant plasma cells in MM patients occasionally express highly immunogenic cancer testis antigens (CTA). CTA expression is regulated by DNA methylation, and may be increased by 5-azacitidine (Celgene corp., Summit, NJ) (Aza), a DNA hypomethylating agent. The addition of lenalidomide (Celgene corp.) (L) may augment any ensuing adoptive CTA-specific immune response. These immune effector cells may then be collected and adoptively transferred in a setting of lympho-depletion and minimal residual disease following SCT, serving a maintenance function. To demonstrate the feasibility of this approach, we initiated a phase II clinical trial of Aza administered sequentially with L ...

Blood, 2013

Histone deacetylase (e.g., vorinostat) and proteasome inhibitors interact synergistically to prom... more Histone deacetylase (e.g., vorinostat) and proteasome inhibitors interact synergistically to promote cell death in various cancer cells, including malignant human hematopoietic cells. The novel, proteasome inhibitor carfilzomib is an attractive candidate for combination regimens due to diminished neurotoxicity, irreversible proteasome inhibition, favorable tolerability profile relative to bortezomib, and preclinical and clinical evidence of activity in bortezomib-resistant cells and patients. Preclinical studies demonstrated synergistic interactions between carfilzomib and vorinostat in human diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells both in vitro and in vivo as well as in bortezomib-resistant cells (Dasmahapatra et al., Blood 115:4478; 2010; Mol Cancer Ther 10:1686, 2001). These preclinical findings prompted a phase 1 trial, using a 3+3 design, with the goal of determining the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) for the comb...

Blood, 2012

3588 Although reports of synergistic interactions between proteasome and histone deacetylase (HDA... more 3588 Although reports of synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in acute leukemias have been limited, they are well described in B-cell malignancies (e.g., myeloma and lymphoma). Nevertheless, preclinical findings have shown striking synergism between the HDAC inhibitor belinostat (previously PXD-101) and the proteasome inhibitor bortezomib, administered at low (sub-micromolar) concentrations, in cultured and primary acute myeloid leukemia (AML) and acute lymphocytic leukemia cells (Dai Y et al. Br J Haematol. 2011). These findings prompted initiation of a phase I trial, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and belinostat in patients with relapsed or refractory acute leukemia, myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blast crisis (CML-BC). To date, 25 patients with the following disease types have been treated: acute leu...

Cardio-Oncology, 2018

Background: Doxorubicin chemotherapy is used across a range of adult and pediatric malignancies. ... more Background: Doxorubicin chemotherapy is used across a range of adult and pediatric malignancies. Cardiac toxicity is common, and dysfunction develops over time in many patients. Biomarkers used for predicting late cardiac dysfunction following doxorubicin exposure have shown promise. Preclinical studies have demonstrated potential cardioprotective effects of sildenafil. Methods: We sought to confirm the safety of adding sildenafil to doxorubicin-based chemotherapy and assess Nterminal Pro-Brain Natriuretic Peptide (NT-proBNP) and high sensitivity cardiac troponin I (hsTnI) as early markers of anthracycline-induced cardiotoxicity. We randomized 27 patients (ages 31-77, 92.3% female) receiving doxorubicin chemotherapy using a blocked randomization scheme with randomly permuted block sizes to receive standard chemotherapy alone or with the addition of sildenafil. The study was not blinded. Sildenafil was dosed at 100 mg by mouth daily during therapy; patients took sildenafil three times daily on the day of doxorubicin. Doxorubicin dosing and schedule were dependent on the treatment regimen. Echocardiography was obtained prior to initiation of treatment and routinely thereafter up to 4 years. NT-proBNP and hsTnI were obtained with each cycle before, 1-3 h after, and 24 h after doxorubicin. Results: Fourteen patients were randomized to receive standard doxorubicin chemotherapy alone (14 treated and analyzed), while 13 patients were randomized to the experimental doxorubicin and sildenafil arm (10 treated and analyzed). No toxicity signal was seen with the addition of sildenafil to doxorubicin-based regimens. There was no statistical difference between the treatment arms in relation to the change of mean left ventricular ejection fraction (LVEF) between the first and last evaluation. In both arms, hsTnI levels increased over time; however, elevated hsTnI was not associated with declines in LVEF. Conclusion: Adding sildenafil was safe, but did not offer cardioprotection following doxorubicin treatment. Increases in hsTnI levels were observed over time, but elevations during therapy did not correlate with subsequent decreases in LVEF. Trial registration: This clinical trial (NCT01375699) was registered at www.clinicaltrials.gov on June 17, 2011.

Cancer Research, 2016

Inhibitor of apoptosis proteins (IAPs e.g., XIAP, cIAP1, cIAP2) inhibit apoptosis through diverse... more Inhibitor of apoptosis proteins (IAPs e.g., XIAP, cIAP1, cIAP2) inhibit apoptosis through diverse mechanisms. Recent attention has focused on novel functions of cIAP1/2, including activation of the canonical and non-canonical NF-κB pathways and inhibition of the extrinsic apoptotic pathway through the ripoptosome. These considerations have stimulated the development of IAP antagonists such as the bivalent IAP inhibitor birinapant (TL-32711). Proteasome inhibitors such as bortezomib are highly active in multiple myeloma (MM), and act, at least in part, by inhibiting NF-κB, raising the possibility of cooperative interactions with IAP antagonists. Synergistic induction of apoptosis was observed in human MM cell lines, including drug-naïve U266 cells, their bortezomib-resistant counterparts (PS-R), and multiple other human MM lines. Birinapant (500 nM) sharply down-regulated cIAP1/2 in MM cells, accompanied by reduced expression of TRAF2, RIP1, and p-IKKβ, as well as robust TRAF3 up-reg...

Blood, 2011

2931 AZD6244 is a potent, selective, oral, non-ATP competitive small molecule inhibitor of the mi... more 2931 AZD6244 is a potent, selective, oral, non-ATP competitive small molecule inhibitor of the mitogen-activated protein kinase, MEK 1/2 that has shown significant pre-clinical activity in multiple myeloma (MM) cells, both in vitro and in vivo, as well as a favorable clinical profile. The present phase II study was designed to determine the response rate for AZD6244 in patients with relapsed or refractory MM. The study utilized a two-stage Simon design to allow for early termination if there was strong evidence of regimen inactivity. Eligible patients were restricted to those with MM who have had at least 2 prior regimens. AZD6244 capsules (75 mg) were administered orally twice daily continuously for 28 day cycles. Response was evaluated after 3 cycles. To date, 37 patients have been enrolled (13 in the 1st stage and 24 in the 2nd stage). One subject enrolled in the 1st stage was not treated. Gender enrollment was balanced (male/female 18/19). The median age of treated patients was ...

Leukemia & Lymphoma, 2020

We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult pa... more We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1000 mg/m2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation.

Blood, 2012

1794 Preclinical studies have demonstrated synergistic interactions between proteasome and histon... more 1794 Preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors in diverse hematologic malignancies, including those of B-cell origin. We have previously shown that the combination of the proteasome inhibitor bortezomib and the HDAC inhibitor romidepsin, administered at extremely low concentrations (∼3–5 nM), results in a striking increase in apoptosis in primary CLL cells, including cells from patients with CLL refractory to standard treatments (Dai Y et al. Clin Cancer Res. 2008). These findings prompted initiation of a phase I trial, using a 3+3 design, with the primary objective of determining the maximum tolerated dose (MTD) for the combination of bortezomib and romidepsin in patients with relapsed or refractory chronic lymphocyte leukemia/small lymphocytic lymphoma (CLL/SLL), indolent B-cell lymphoma, or peripheral T-cell lymphoma (PTCL). To date, 11 patients have been enrolled and treated. All of the patients tr...

Clinical Cancer Research, 2013

Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocid... more Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination. Experimental Design: Patients received vorinostat (200 mg orally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily × 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly × 2. The alvocidib dose was escalated using a standard 3+3 design. Results: Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m2 (30-minute loading infusion) followed by 20 mg/m2 (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities we...

British Journal of Haematology, 2012

Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transpl... more Patients with multiple myeloma (MM) undergoing high dose therapy and autologous stem cell transplantation (SCT) remain at risk for disease progression. Induction of the expression of highly immunogenic cancer testis antigens (CTA) in malignant plasma cells in MM patients may trigger a protective immune response following SCT. We initiated a phase II clinical trial of the DNA hypomethylating agent, azacitidine (Aza) administered sequentially with lenalidomide (Rev) in patients with MM. Three cycles of Aza and Rev were administered and autologous lymphocytes were collected following the 2nd and 3rd cycles of Aza-Rev and cryopreserved. Subsequent stem cell mobilization was followed by high-dose melphalan and SCT. Autologous lymphocyte infusion (ALI) was performed in the second month following transplantation. Fourteen patients have

Biology of Blood and Marrow Transplantation, 2011

to support one over the others. We historically used CSA/MTX (n 5 187 pts). Over the last 3 years... more to support one over the others. We historically used CSA/MTX (n 5 187 pts). Over the last 3 years we used CSA/MMF (n 5 92). Median pt age was 52 years (18-73). Diagnoses included AML/MDS (n 5 152), ALL (n 5 30), CML (n 5 12), myeloma (n 5 24), lymphoma (n 5 40), others (n 5 21). The donor was 10/10 (n 5 191), 9/10 (n 5 54) or # 8/ 10 match (n 5 34). Conditioning was myeloablative (n 5 58) or reduced intensity/toxicity (RIC, n 5 221). Non-relapse mortality (NRM) is dependant on regimen toxicity and GVHD. CSA/MMF was less toxic than CSA/MTX. It allowed faster engraftment, day +11 and +14, respectively (p \ 0.001). Day30 mortality was 2.2% and 10.7%, respectively (p 5 0.04). Multivariate analysis (MVA) identified high comorbidity index (HR 2.5, p 5 0.05), advanced disease (HR 6.2, p 5 0.005), mismatched donor (HR 2.4, p 5 0.03) and lymphoid malignancies (HR 2.8, p 5 0.03) as adverse factors for regimen-related mortality. CSA/MMF was protective (HR 0.4, p 5 0.02). However, CSA/MMF was less effective in preventing grade III-IV acute GVHD; cumulative incidence 29% and 18%, respectively (p 5 0.005). MVA identified mismatched donor (HR 3.4, p 5 0.001) and CSA/MMF (HR 2.4, p 5 0.004) as adverse factors, while RIC was protective (HR 0.4, p 5 0.01). The net effect was that NRM was equivalent with both regimens. GVHD regimen had major impact on overall survival (OS) when pts were stratified based on disease status. In early stage disease, OS was 65% and 42%, after CSA/MTX and CSA/MMF, respectively (HR 1.9, p 5 0.05), predominantly due to excess GVHD deaths in the MMF group. In advanced disease, OS was better with CSA/MMF; 20% and 12%, respectively (HR 0.5, p 5 0.04), predominantly due to less relapses. In conclusion, GVHD prevention regimen has major impact on outcome after MUD SCT. CSA/MMF is a less toxic regimen and allows prompt engraftment, but is less effective in preventing GVHD. In early stage disease, outcome is dominated by NRM and more effective GVHD prevention regimen such as CSA/MTX is needed. In advanced disease both toxicity and relapse increase. A less intensive regimen, that also better preserves GVL, such as CSA/MMF, may be associated with better outcome. The GVHD prevention regimen selected may need to be tailored to pt and disease characteristics.