Therapeutics For Hematological Malignancies Research Articles

Characterization of stem cell landscape and assessing the stemness degree to aid clinical therapeutics in hematologic malignancies

Hematological malignancies are a group of cancers that affect the blood, bone marrow, and lymphatic system. Cancer stem cells (CSCs) are believed to be responsible for the initiation, progression, and relapse of hematological malignancies. However, identifying and targeting CSCs presents many challenges. We aimed to develop a stemness index (HSCsi) to identify and guide the therapy targeting CSCs in hematological malignancies. We developed a novel one-class logistic regression (OCLR) algorithm to identify transcriptomic feature sets related to stemness in hematologic malignancies. We used the HSCsi to measure the stemness degree of leukemia stem cells (LSCs) and correlate it with clinical outcomes.We analyze the correlation of HSCsi with genes and pathways involved in drug resistance and immune microenvironment of acute myeloid leukemia (AML). HSCsi revealed stemness-related biological mechanisms in hematologic malignancies and effectively identify LSCs. The index also predicted survival and relapse rates of various hematologic malignancies. We also identified potential drugs and interventions targeting cancer stem cells (CSCs) of hematologic malignancies by the index. Moreover, we found a correlation between stemness and bone marrow immune microenvironment in AML. Our study provides a novel method and tool to assess the stemness degree of hematologic malignancies and its implications for clinical outcomes and therapeutic strategies. Our HSC stemness index can facilitate the precise stratification of hematologic malignancies, suggest possible targeted and immunotherapy options, and guide the selection of patients.

The Relevance of Aurora Kinase Inhibition in Hematological Malignancies.

Aurora kinases are a family of serine/threonine protein kinases that play a central role in eukaryotic cell division. Overexpression of aurora kinases in cancer and their role as major regulators of the cell cycle quickly inspired the idea that their inhibition might be a potential pathway when treating oncologic patients. Over the past couple of decades, the search for designing and testing of molecules capable of inhibiting aurora activities fueled many pre-clinical and clinical studies. In this study, data from the past 10 years of in vitro and in vivo investigations, as well as clinical trials, utilizing aurora kinase inhibitors as therapeutics for hematological malignancies were compiled and discussed, aiming to highlight potential uses of these inhibitors as a novel monotherapy model or alongside conventional chemotherapies. While there is still much to be elucidated, it is clear that these kinases play a key role in oncogenesis, and their manageable toxicity and potentially synergistic effects still render them a focus of interest for future investigations in combinatorial clinical trials.

Abstract IA16: Acquired resistance to targeted therapeutics in hematologic malignancies

Abstract Targeted treatment approaches of hematologic malignancies provided many of the first inroads into the successful treatment of human malignancy with the emerging class of targeted therapeutics. Initial responsiveness to targeted therapy provides compelling evidence for the importance of specific targets for the maintenance of disease. Understanding mechanisms of acquired resistance further informs how malignant cells can circumvent target inhibition in patients, and in some instances, these insights have facilitated the successful development of next generation targeted therapeutics, best exemplified by BCR-ABL tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia (CML). As detailed genomic analyses are becoming more readily available, opportunities for developing and incorporating targeted therapeutics are expected to increase. It is becoming clear, however, that tumor heterogeneity in advanced hematologic malignancies can be substantial, and resistant subclones can compromise duration of response to targeted therapy. Several examples of acquired resistance to targeted therapeutics in human hematopoietic malignancies will be presented, as well as the implications of these molecular mechanisms toward future successful management of these diseases. Citation Format: Neil P. Shah. Acquired resistance to targeted therapeutics in hematologic malignancies. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA16.

Targeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia

AbstractSeveral RNA-targeted therapeutics, including antisense oligonucleotides (ONs), small interfering RNAs, and miRNAs, constitute immunostimulatory CpG motifs as an integral part of their design. The limited success with free antisense ONs in hematologic malignancies in recent clinical trials has been attributed to the CpG motif–mediated, TLR-induced prosurvival effects and inefficient target modulation in desired cells. In an attempt to diminish their off-target prosurvival and proinflammatory effects and specific delivery, as a proof of principle, in the present study, we developed an Ab-targeted liposomal delivery strategy using a clinically relevant CD20 Ab (rituximab)–conjugated lipopolyplex nanoparticle (RIT-INP)– and Bcl-2–targeted antisense G3139 as archetypical antisense therapeutics. The adverse immunostimulatory responses were abrogated by selective B cell–targeted delivery and early endosomal compartmentalization of G3139-encapsulated RIT-INPs, resulting in reduced NF-κB activation, robust Bcl-2 down-regulation, and enhanced sensitivity to fludarabine-induced cytotoxicity. Furthermore, significant in vivo therapeutic efficacy was noted after RIT-INP–G3139 administration in a disseminated xenograft leukemia model. The results of the present study demonstrate that CD20-targeted delivery overcomes the immunostimulatory properties of CpG-containing ON therapeutics and improves efficient gene silencing and in vivo therapeutic efficacy for B-cell malignancies. The broader implications of similar approaches in overcoming immunostimulatory properties of RNA-directed therapeutics in hematologic malignancies are also discussed.

The PIM kinases in hematological cancers

The PIM genes represent a family of proto-oncogenes that encode three different serine/threonine protein kinases (PIM1, PIM2 and PIM3) with essential roles in the regulation of signal transduction cascades, which promote cell survival, proliferation and drug resistance. PIM kinases are overexpressed in several hematopoietic tumors and support in vitro and in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis. PIM kinases do not have an identified regulatory domain, which means that these proteins are constitutively active once transcribed. They appear to be critical downstream effectors of important oncoproteins and, when overexpressed, can mediate drug resistance to available agents, such as rapamycin. Recent crystallography studies reveal that, unlike other kinases, they possess a hinge region, which creates a unique binding pocket for ATP, offering a target for an increasing number of potent small-molecule PIM kinase inhibitors. Preclinical studies in models of various hematologic cancers indicate that these novel agents show promising activity and some of them are currently being evaluated in a clinical setting. In this review, we profile the PIM kinases as targets for therapeutics in hematologic malignancies.

Inhibiting the palmitoylation/depalmitoylation cycle selectively reduces the growth of hematopoietic cells expressing oncogenic Nras

AbstractThe palmitoylation/depalmitoylation cycle of posttranslational processing is a potential therapeutic target for selectively inhibiting the growth of hematologic cancers with somatic NRAS mutations. To investigate this question at the single-cell level, we constructed murine stem cell virus vectors and assayed the growth of myeloid progenitors. Whereas cells expressing oncogenic N-RasG12D formed cytokine-independent colonies and were hypersensitive to GM-CSF, mutations within the N-Ras hypervariable region induced N-Ras mislocalization and attenuated aberrant progenitor growth. Exposing transduced hematopoietic cells and bone marrow from Nras and Kras mutant mice to the acyl protein thioesterase inhibitor palmostatin B had similar effects on protein localization and colony growth. Importantly, palmostatin B-mediated inhibition was selective for Nras mutant cells, and we mapped this activity to the hypervariable region. These data support the clinical development of depalmitoylation inhibitors as a novel class of rational therapeutics in hematologic malignancies with NRAS mutations.

SU11657 Cooperates with Doxorubicin To Increase Survival of Leukemic Mice.

Acute promyelocytic leukemia (APL) is characterized by t(15,17) resulting in fusion of RARα to PML; in rare cases, RARα may be fused to other partners. The PML-RARα fusion initiates APL-like disease in mice, including a response to ATRA. FLT3, a receptor tyrosine kinase, is mutated in a large number of human AMLs and roughly 40% of cases of human APL. In our mouse model of APL, we previously introduced activated FLT3 (ITD mutation) into bone marrow of PML-RARα transgenic mice and observed rapid development of AML. This disease is transplantable into sublethally irradiated mice with onset of disease between 3–6 weeks, creating a system suitable for therapeutic study.There has been considerable effort focused on the development of small molecule inhibitors of FLT3 as therapeutics for hematological malignancies, in particular, AML; some of these inhibitors are currently in clinical trials. SU11657 is a multi-targeted inhibitor of class III/V receptor tyrosine kinases, including FLT3. We previously observed a synergistic effect of SU11657 in combination with ATRA in our PML-RARα/FLT3 model. We set out to use this model to assess the effectiveness of anthracycline chemotherapy in combination with SU11657. This model is in vivo resistant to the maximum tolerated dose of doxorubicin (3 mg/kg/day).We found that the median survival of untreated and doxorubicin-treated mice with PML-RARα/FLT3 leukemia was not significantly different (42 and 45 days, respectively). SU11657 increased the median of survival to 55 days, whereas the combination therapy increased median survival to 62 days (P=0.003). Neither agent alone or in combination significantly increased survival of mice with PML-RARα leukemia lacking activated FLT3. These results suggest that the use of targeted therapeutics, such as a FLT3 inhibitor, can overcome chemoresistance to traditional therapies in AMLs.