Prithviraj Bose - Academia.edu (original) (raw)

Papers by Prithviraj Bose

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 7, 2015

AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma (MM) cell... more AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma (MM) cells. This phase 2 study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory MM. AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after 3 cycles. Thirty-six patients received therapy. The median age was 65 years (range: 43-81) and the median number of prior therapies was 5 (range: 2-11). The most common grade 3 and 4 toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three deaths occurred possibly related to AZD6244 (2 due to sepsis, 1 due to acute kidney injury). After AZD6244 discontinuation, 3 additional deaths occurred due to disease progression. The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response (VGPR), 1 ...

A model disease in many respects, chronic myelogenous leukemia (CML) has been called the pristine... more A model disease in many respects, chronic myelogenous leukemia (CML) has been called the pristine paradigm for molecularly targeted therapy. Bcr-Abl tyrosine kinase inhibitors (TKIs) have dramatically altered the therapeutic landscape of CML, so much so that many patients diagnosed in chronic phase and treated appropriately now enjoy a life expectancy similar to that of the general population. However, despite the enormous strides made in advancing therapy for this disease, it remains, for the most part, incurable except by allogeneic hematopoietic stem cell transplantation (HSCT). For patients, this means a lifelong commitment to daily TKI therapy. These agents are expensive, and not without side effects, making cure a highly desirable and worthwhile goal. Multiple studies have shown that in contrast to their impressive efficacy against proliferating CML cells, TKIs are unable to eradicate the tiny fraction of quiescent stem cells that are responsible for disease persistence and recurrence upon TKI discontinuation. This has fueled efforts to better understand CML stem cell biology and elucidate survival pathways unique to these cells, the targeted interruption of which could potentially synergize with Bcr-Abl TKIs to confer synthetic lethality while sparing normal hematopoietic stem cells (HSCs). The molecular pathogenesis of CML and mechanisms of resistance to TKIs are reviewed in detail elsewhere in this volume. In this chapter, we provide a brief overview of these topics, summarize key concepts relating to CML stem cell biology, and discuss strategies to effectively target this difficult-to-kill population that might one day result in a cure for CML.

Leukemia & lymphoma, Jan 18, 2015

A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vor... more A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30 min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3+3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m(2) carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and 2 patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response. Trial Registration ID: NCT01276717.

Journal of clinical medicine, 2015

Despite modest improvements in survival over the last several decades, the treatment of AML conti... more Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex biology of AML continues to be elucidated, many "synthetic lethal" strategies involving rational combinations of targeted agents have been developed. Unfortunately, relatively few of these have been tested clinically, although there is growing interest in this area. In this art...

Adenocarcinoma of the exocrine pancreas continues to challenge clinicians and investigators world... more Adenocarcinoma of the exocrine pancreas continues to challenge clinicians and investigators worldwide. The remarkable paucity of effective therapies has meant that the median survival of patients with metastatic disease has ranged from six months to a year at best. For years, gemcitabine has been the cornerstone of treatment, after it was shown to modestly improve survival and confer a significant clinical benefit when compared to fluorouracil. Since then, many attempts to build upon the gemcitabine backbone with the addition of a variety of cytotoxic and targeted agents have failed, with the notable exception of erlotinib; however, the magnitude of the improvement in survival with the addition of this agent to gemcitabine was small. Recently, FOLFIRINOX was established as a new standard of care for patients with an excellent performance status. This significant advance notwithstanding, there remains much room for improvement. Fortunately, we have gained considerable insights into t...

Expert review of hematology, 2012

Leukemia research reports, 2013

Despite the remarkable success of imatinib against Bcr-Abl, development of secondary resistance, ... more Despite the remarkable success of imatinib against Bcr-Abl, development of secondary resistance, most often due to point mutations in the Bcr-Abl tyrosine kinase (TK) domain, is quite common. Of these, the T315I "gatekeeper" mutation is resistant to all currently registered Bcr-Abl TK inhibitors (TKIs) with the notable exception of ponatinib (Iclusig™), which was very recently approved by the United States Food and Drug Administration (FDA). Besides ponatinib, numerous strategies have been developed to circumvent this problem. These include the protein synthesis inhibitor omacetaxine (Synribo®), and "switch-control" inhibitors. Dual Bcr-Abl and aurora kinase inhibitors represent another promising strategy. Finally, several promising synergistic combinations, such as TKIs with histone deacetylase inhibitors (HDACIs), warrant attention.

Leukemia Research Reports, 2013

The B-cell lymphoma-2 (Bcl-2) family of proteins regulates the intrinsic, or mitochondrial pathwa... more The B-cell lymphoma-2 (Bcl-2) family of proteins regulates the intrinsic, or mitochondrial pathway of apoptosis, the final common mechanism of cell death in response to a variety of physiologic and pharmacologic signals, and plays a central role in AML pathogenesis, prognosis and responsiveness to chemotherapy. Traditionally thought to be an important survival factor for multiple myeloma cells, the anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) has recently been shown in preclinical studies to be critical to the development and maintenance of AML, making it an attractive therapeutic target in this disease. Several characteristics, such as its very short half-life, distinguish Mcl-1 from other anti-apoptotic Bcl-2 family members. Additionally, Mcl-1 levels are regulated by a large number of pathways affecting its transcription, translation and degradation. A variety of approaches exploiting these features have been developed to inhibit directly or indirectly the antiapoptotic function of Mcl-1. Many of these lend themselves well to combination therapies, leading to striking synergism, at least in preclinical models. In this brief review, we highlight some of the more promising strategies targeting Mcl-1 in AML, with a particular emphasis on rational combinations of novel agents.

Resistance to Targeted Anti-Cancer Therapeutics, 2014

Expert Opinion on Pharmacotherapy, 2014

Bortezomib , the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the US... more Bortezomib , the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the USA and Europe for the treatment of patients with multiple myeloma, and in the USA for patients with relapsed mantle cell lymphoma (MCL). This review examines the role of bortezomib in the therapy of non-Hodgkin's lymphoma (NHL). Bortezomib may be particularly effective against the NF-κB-dependent activated B-cell subtype of diffuse large B-cell lymphoma. The combination of bortezomib with rituximab and dexamethasone represents a standard approach for the treatment of Waldenström's macroglobulinemia, and that with bendamustine and rituximab has demonstrated excellent efficacy in follicular lymphoma. Combinations with other novel agents, such as inhibitors of cyclin-dependent kinases or histone deacetylases, also hold substantial promise in NHL. Unmet needs in NHL, competitor compounds, chemistry, pharmacokinetics, pharmacodynamics and safety and tolerability of bortezomib are also discussed. The success of bortezomib in MCL has validated the proteasome as a therapeutic target in NHL. Rational combinations, for example, with Bruton's tyrosine kinase inhibitors or BH3-mimetics, may hold the key to optimizing the therapeutic potential of PIs in NHL. Future trials are likely to involve newer agents with improved pharmacodynamic (e.g., carfilzomib, marizomib) or pharmacokinetic (e.g., ixazomib, oprozomib) properties.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2014

This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tole... more This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma). Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic t...

Targeted Therapy of Acute Myeloid Leukemia, 2014

ABSTRACT The Bcl-2 family of antiapoptotic and proapoptotic proteins serve as key regulators of t... more ABSTRACT The Bcl-2 family of antiapoptotic and proapoptotic proteins serve as key regulators of the mitochondrial pathway of apoptosis. Multiple signals from a variety of cell death stimuli converge upon mitochondria to trigger the intrinsic apoptotic cascade. Bcl-2 family proteins are intimately related to prognosis and therapeutic resistance in acute myeloid leukemia (AML), making them rational targets for drug development. Also, directly targeting Bcl-2 family proteins circumvents many of the problems associated with targeting upstream molecules. The Bcl-2 antisense oligonucleotide oblimersen failed to live up to its initial promise in large phase III trials. The discovery of ABT-737, a novel, small-molecule inhibitor of specific protein–protein interactions, gave a much-needed impetus to the field of “BH3 mimetic” research. The demonstration that Mcl-1, an antiapoptotic Bcl-2 family protein that is not inhibited by ABT-737 or its analogs, is of crucial importance in AML, underscores the need for rational drug combinations that simultaneously target multiple arms of the apoptotic regulatory machinery.

Gastrointestinal Stromal Tumor, 2012

Case Reports in Hematology, 2014

Myeloid sarcoma represents the proliferation of myeloblasts of acute myeloid leukemia (AML) at ex... more Myeloid sarcoma represents the proliferation of myeloblasts of acute myeloid leukemia (AML) at extramedullary sites. While extramedullary involvement in AML is uncommon in itself, isolated myeloid sarcomas, that is, myeloid sarcomas without any bone marrow involvement, are extremely rare and pose a diagnostic and therapeutic challenge. Here, we present the case of a middle-aged woman with isolated myeloid sarcoma in the stomach-an organ seldom involved by this disease. Additionally, the literature on the epidemiology, diagnosis, pathology, prognosis, and therapeutic options in myeloid sarcomas has been reviewed.

Physiological Genomics, 2014

Acute myeloid leukemia (AML) continues to represent an area of critical unmet need with respect t... more Acute myeloid leukemia (AML) continues to represent an area of critical unmet need with respect to new and effective targeted therapies. The Bcl-2 family of pro- and antiapoptotic proteins stands at the crossroads of cellular survival and death, and the expression of and interactions between these proteins determine tumor cell fate. Malignant cells, which are often primed for apoptosis, are particularly vulnerable to the simultaneous disruption of cooperative survival signaling pathways. Indeed, the single agent activity of agents such as mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase (MEK) inhibitors in AML has been modest. Much work in recent years has focused on strategies to enhance the therapeutic potential of the bona fide BH3-mimetic, ABT-737, which inhibits B-cell lymphoma 2 (Bcl-2) and Bcl-xL. Most of these strategies target Mcl-1, an antiapoptotic protein not inhibited by ABT-737. The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways are central to the growth, proliferation, and survival of AML cells, and there is much interest currently in pharmacologically interrupting these pathways. Dual inhibitors of PI3K and mTOR overcome some intrinsic disadvantages of rapamycin and its derivatives, which selectively inhibit mTOR. In this review, we discuss why combining dual PI3K/mTOR blockade with inhibition of Bcl-2 and Bcl-xL, by virtue of allowing coordinate inhibition of three mutually synergistic pathways in AML cells, may be a particularly attractive therapeutic strategy in AML, the success of which may be predicted for by basal Akt activation.

Pharmacology & Therapeutics, 2014

Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling vi... more Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clinical studies. In recent years, additional mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clinical potential, the clinical use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discusses synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 7, 2015

AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma (MM) cell... more AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma (MM) cells. This phase 2 study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory MM. AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after 3 cycles. Thirty-six patients received therapy. The median age was 65 years (range: 43-81) and the median number of prior therapies was 5 (range: 2-11). The most common grade 3 and 4 toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three deaths occurred possibly related to AZD6244 (2 due to sepsis, 1 due to acute kidney injury). After AZD6244 discontinuation, 3 additional deaths occurred due to disease progression. The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response (VGPR), 1 ...

A model disease in many respects, chronic myelogenous leukemia (CML) has been called the pristine... more A model disease in many respects, chronic myelogenous leukemia (CML) has been called the pristine paradigm for molecularly targeted therapy. Bcr-Abl tyrosine kinase inhibitors (TKIs) have dramatically altered the therapeutic landscape of CML, so much so that many patients diagnosed in chronic phase and treated appropriately now enjoy a life expectancy similar to that of the general population. However, despite the enormous strides made in advancing therapy for this disease, it remains, for the most part, incurable except by allogeneic hematopoietic stem cell transplantation (HSCT). For patients, this means a lifelong commitment to daily TKI therapy. These agents are expensive, and not without side effects, making cure a highly desirable and worthwhile goal. Multiple studies have shown that in contrast to their impressive efficacy against proliferating CML cells, TKIs are unable to eradicate the tiny fraction of quiescent stem cells that are responsible for disease persistence and recurrence upon TKI discontinuation. This has fueled efforts to better understand CML stem cell biology and elucidate survival pathways unique to these cells, the targeted interruption of which could potentially synergize with Bcr-Abl TKIs to confer synthetic lethality while sparing normal hematopoietic stem cells (HSCs). The molecular pathogenesis of CML and mechanisms of resistance to TKIs are reviewed in detail elsewhere in this volume. In this chapter, we provide a brief overview of these topics, summarize key concepts relating to CML stem cell biology, and discuss strategies to effectively target this difficult-to-kill population that might one day result in a cure for CML.

Leukemia & lymphoma, Jan 18, 2015

A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vor... more A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30 min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3+3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m(2) carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and 2 patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response. Trial Registration ID: NCT01276717.

Journal of clinical medicine, 2015

Despite modest improvements in survival over the last several decades, the treatment of AML conti... more Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex biology of AML continues to be elucidated, many "synthetic lethal" strategies involving rational combinations of targeted agents have been developed. Unfortunately, relatively few of these have been tested clinically, although there is growing interest in this area. In this art...

Adenocarcinoma of the exocrine pancreas continues to challenge clinicians and investigators world... more Adenocarcinoma of the exocrine pancreas continues to challenge clinicians and investigators worldwide. The remarkable paucity of effective therapies has meant that the median survival of patients with metastatic disease has ranged from six months to a year at best. For years, gemcitabine has been the cornerstone of treatment, after it was shown to modestly improve survival and confer a significant clinical benefit when compared to fluorouracil. Since then, many attempts to build upon the gemcitabine backbone with the addition of a variety of cytotoxic and targeted agents have failed, with the notable exception of erlotinib; however, the magnitude of the improvement in survival with the addition of this agent to gemcitabine was small. Recently, FOLFIRINOX was established as a new standard of care for patients with an excellent performance status. This significant advance notwithstanding, there remains much room for improvement. Fortunately, we have gained considerable insights into t...

Expert review of hematology, 2012

Leukemia research reports, 2013

Despite the remarkable success of imatinib against Bcr-Abl, development of secondary resistance, ... more Despite the remarkable success of imatinib against Bcr-Abl, development of secondary resistance, most often due to point mutations in the Bcr-Abl tyrosine kinase (TK) domain, is quite common. Of these, the T315I "gatekeeper" mutation is resistant to all currently registered Bcr-Abl TK inhibitors (TKIs) with the notable exception of ponatinib (Iclusig™), which was very recently approved by the United States Food and Drug Administration (FDA). Besides ponatinib, numerous strategies have been developed to circumvent this problem. These include the protein synthesis inhibitor omacetaxine (Synribo®), and "switch-control" inhibitors. Dual Bcr-Abl and aurora kinase inhibitors represent another promising strategy. Finally, several promising synergistic combinations, such as TKIs with histone deacetylase inhibitors (HDACIs), warrant attention.

Leukemia Research Reports, 2013

The B-cell lymphoma-2 (Bcl-2) family of proteins regulates the intrinsic, or mitochondrial pathwa... more The B-cell lymphoma-2 (Bcl-2) family of proteins regulates the intrinsic, or mitochondrial pathway of apoptosis, the final common mechanism of cell death in response to a variety of physiologic and pharmacologic signals, and plays a central role in AML pathogenesis, prognosis and responsiveness to chemotherapy. Traditionally thought to be an important survival factor for multiple myeloma cells, the anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) has recently been shown in preclinical studies to be critical to the development and maintenance of AML, making it an attractive therapeutic target in this disease. Several characteristics, such as its very short half-life, distinguish Mcl-1 from other anti-apoptotic Bcl-2 family members. Additionally, Mcl-1 levels are regulated by a large number of pathways affecting its transcription, translation and degradation. A variety of approaches exploiting these features have been developed to inhibit directly or indirectly the antiapoptotic function of Mcl-1. Many of these lend themselves well to combination therapies, leading to striking synergism, at least in preclinical models. In this brief review, we highlight some of the more promising strategies targeting Mcl-1 in AML, with a particular emphasis on rational combinations of novel agents.

Resistance to Targeted Anti-Cancer Therapeutics, 2014

Expert Opinion on Pharmacotherapy, 2014

Bortezomib , the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the US... more Bortezomib , the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the USA and Europe for the treatment of patients with multiple myeloma, and in the USA for patients with relapsed mantle cell lymphoma (MCL). This review examines the role of bortezomib in the therapy of non-Hodgkin's lymphoma (NHL). Bortezomib may be particularly effective against the NF-κB-dependent activated B-cell subtype of diffuse large B-cell lymphoma. The combination of bortezomib with rituximab and dexamethasone represents a standard approach for the treatment of Waldenström's macroglobulinemia, and that with bendamustine and rituximab has demonstrated excellent efficacy in follicular lymphoma. Combinations with other novel agents, such as inhibitors of cyclin-dependent kinases or histone deacetylases, also hold substantial promise in NHL. Unmet needs in NHL, competitor compounds, chemistry, pharmacokinetics, pharmacodynamics and safety and tolerability of bortezomib are also discussed. The success of bortezomib in MCL has validated the proteasome as a therapeutic target in NHL. Rational combinations, for example, with Bruton's tyrosine kinase inhibitors or BH3-mimetics, may hold the key to optimizing the therapeutic potential of PIs in NHL. Future trials are likely to involve newer agents with improved pharmacodynamic (e.g., carfilzomib, marizomib) or pharmacokinetic (e.g., ixazomib, oprozomib) properties.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 15, 2014

This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tole... more This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma). Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic t...

Targeted Therapy of Acute Myeloid Leukemia, 2014

ABSTRACT The Bcl-2 family of antiapoptotic and proapoptotic proteins serve as key regulators of t... more ABSTRACT The Bcl-2 family of antiapoptotic and proapoptotic proteins serve as key regulators of the mitochondrial pathway of apoptosis. Multiple signals from a variety of cell death stimuli converge upon mitochondria to trigger the intrinsic apoptotic cascade. Bcl-2 family proteins are intimately related to prognosis and therapeutic resistance in acute myeloid leukemia (AML), making them rational targets for drug development. Also, directly targeting Bcl-2 family proteins circumvents many of the problems associated with targeting upstream molecules. The Bcl-2 antisense oligonucleotide oblimersen failed to live up to its initial promise in large phase III trials. The discovery of ABT-737, a novel, small-molecule inhibitor of specific protein–protein interactions, gave a much-needed impetus to the field of “BH3 mimetic” research. The demonstration that Mcl-1, an antiapoptotic Bcl-2 family protein that is not inhibited by ABT-737 or its analogs, is of crucial importance in AML, underscores the need for rational drug combinations that simultaneously target multiple arms of the apoptotic regulatory machinery.

Gastrointestinal Stromal Tumor, 2012

Case Reports in Hematology, 2014

Myeloid sarcoma represents the proliferation of myeloblasts of acute myeloid leukemia (AML) at ex... more Myeloid sarcoma represents the proliferation of myeloblasts of acute myeloid leukemia (AML) at extramedullary sites. While extramedullary involvement in AML is uncommon in itself, isolated myeloid sarcomas, that is, myeloid sarcomas without any bone marrow involvement, are extremely rare and pose a diagnostic and therapeutic challenge. Here, we present the case of a middle-aged woman with isolated myeloid sarcoma in the stomach-an organ seldom involved by this disease. Additionally, the literature on the epidemiology, diagnosis, pathology, prognosis, and therapeutic options in myeloid sarcomas has been reviewed.

Physiological Genomics, 2014

Acute myeloid leukemia (AML) continues to represent an area of critical unmet need with respect t... more Acute myeloid leukemia (AML) continues to represent an area of critical unmet need with respect to new and effective targeted therapies. The Bcl-2 family of pro- and antiapoptotic proteins stands at the crossroads of cellular survival and death, and the expression of and interactions between these proteins determine tumor cell fate. Malignant cells, which are often primed for apoptosis, are particularly vulnerable to the simultaneous disruption of cooperative survival signaling pathways. Indeed, the single agent activity of agents such as mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase (MEK) inhibitors in AML has been modest. Much work in recent years has focused on strategies to enhance the therapeutic potential of the bona fide BH3-mimetic, ABT-737, which inhibits B-cell lymphoma 2 (Bcl-2) and Bcl-xL. Most of these strategies target Mcl-1, an antiapoptotic protein not inhibited by ABT-737. The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways are central to the growth, proliferation, and survival of AML cells, and there is much interest currently in pharmacologically interrupting these pathways. Dual inhibitors of PI3K and mTOR overcome some intrinsic disadvantages of rapamycin and its derivatives, which selectively inhibit mTOR. In this review, we discuss why combining dual PI3K/mTOR blockade with inhibition of Bcl-2 and Bcl-xL, by virtue of allowing coordinate inhibition of three mutually synergistic pathways in AML cells, may be a particularly attractive therapeutic strategy in AML, the success of which may be predicted for by basal Akt activation.

Pharmacology & Therapeutics, 2014

Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling vi... more Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clinical studies. In recent years, additional mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clinical potential, the clinical use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discusses synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer.