Triona Ni Chonghaile

Royal College of Surgeons in Ireland | RCSI · Department of Physiology and Medical Physics

Cytotoxic chemotherapy targets elements common to all nucleated human cells, such as DNA and microtubules, yet it selectively kills tumor cells. Here we show that clinical response to these drugs correlates with, and may be partially governed by, the pretreatment proximity of tumor cell mitochondria to the apoptotic threshold, a property called mit...

Unlabelled: Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy derived from immature B-lymphoid and T-lymphoid cells (T-ALL). In T-ALL, there is an early T-cell progenitor (ETP) subgroup that has a very high risk for relapse. In this study, we used mitochondrial BH3 profiling to determine antiapoptotic protein dependencies in T-ALL....

T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive hematologic malignancy arising from the transformation of immune T-cell lymphocytes. Early T-cell progenitor (ETP-ALL) is a subgroup particularly associated with a poor prognosis and a high risk for relapse. While the leukaemia initially develops in the thymus it spreads in the blood to...

Triple-negative breast cancer (TNBC) is a subtype of breast cancer without a targeted form of therapy. Unfortunately, up to 70% of patients with TNBC develop resistance to treatment. A known contributor to chemoresistance is dysfunctional mitochondrial apoptosis signaling. We set up a phenotypic small-molecule screen to reveal vulnerabilities in TN...

Introduction: In KRAS-mutant non-small lung cancer (NSCLC), co-occurring alterations in LKB1 confer a negative prognosis compared to other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetical inhibition of HDAC6 demonstrated im...

Venetoclax is a B cell lymphoma 2 (BCL-2)–selective antagonist used to treat chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). Although this has been a promising therapeutic option for these patients, many of these patients develop resistance and relapsed disease. Here, we summarize the emerging mechanisms of resistance to ve...

The first example of a Pt complex of GANT61, a hedgehog (Hh) pathway inhibitor is reported. Reaction of cis-[Pt(II)Cl2(dmso)2] with one equivalent of 4-pyridine carboxaldehyde (4-PCA, control ligand) or one equivalent of GANT61 (Hh pathway inhibitor) in acetone at rt for 30 minutes afforded trans-[Pt(II)Cl2(dmso)(4-PCA)] (1) and trans-[Pt(II)Cl2(dm...

Resistance to mitochondrial apoptosis predicts inferior treatment outcomes in patients with diverse tumor types, including T-cell acute lymphoblastic leukemia (T-ALL). However, the genetic basis for variability in this mitochondrial apoptotic phenotype is poorly understood, preventing its rational therapeutic targeting. Using BH3 profiling and exon...

Multiple Myeloma (MM) is a haematological malignancy characterised by clonal proliferation of plasma cells within the bone marrow (Landgren and Weiss, 2009). Unfortunately, despite the major improvements to the treatment of MM within the last decade, it remains an incurable disease. Therefore, novel innovative combinations of less toxic therapies a...

T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive hematologic malignancy arising from the transformation of immune T-cell lymphocytes. Early T-cell progenitor (ETP-ALL) is a subgroup particularly associated with chemoresistance and a high risk for relapse. Recently, it was shown that ETP-ALL is dependent on the expression of the anti-ap...

Due to developments in modern chemistry, previously undruggable targets are becoming druggable thanks to selective degradation using the ubiquitin-proteasomal degradation system. PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules designed specifically to degrade target proteins (protein of interest, POI). They are of signific...

Multiple Myeloma (MM) is a malignancy of the antibody-producing plasma cells. Despite improvements to treatment throughout the years, it remains an incurable and fatal disease [1]. Therefore, novel innovative therapies are needed for relapsed/refractory MM. The anti-apoptotic BCL-2 family of proteins (BCL-2, BCL-XL and MCL-1) are critical regulator...

B-cell lymphoma 2 (BCL-2) has recently emerged as a therapeutic target for early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL), a high-risk subtype of human T-cell ALL. The major clinical challenge with targeted therapeutics, such as the BCL-2 inhibitor ABT-199, is the development of acquired resistance. We assessed the in vivo response...

Metabolic reprogramming is a hallmark of cancer which contributes to essential processes required for cell survival, growth, and proliferation. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and its genomic classification has given rise to the design of therapies targeting tumors harboring specific gene alterations that c...

Approximately 70% of breast cancers express estrogen receptor α (ERα) and depend on this key transcriptional regulator for proliferation and differentiation. While patients with this disease can be treated with targeted antiendocrine agents, drug resistance remains a significant issue, with almost half of patients ultimately relapsing. Elucidating...

Invasive lobular carcinoma (ILC) is the second most common type of breast cancer after invasive ductal carcinoma (IDC), accounting for approximately 10-15% of all breast tumors. ILC is characterized by inactivation of E-Cadherin and neoplastic cells that invade the stroma in a "single-file" pattern. Women with ILC are usually older, have used hormo...

Purpose: Invasive lobular carcinoma (ILC) is a subtype of breast cancer accounting for 10% of breast tumors. The majority of patients are treated with endocrine therapy; however, endocrine resistance is common in estrogen receptor-positive breast cancer and new therapeutic strategies are needed. Bromodomain and extraterminal inhibitors (BETi) are...

Recent studies suggest that mild hypoxia-induced neonatal seizures can trigger an acute neuroinflammatory response leading to long-lasting changes in brain excitability along with associated cognitive and behavioral deficits. The cellular elements and signaling pathways underlying neuroinflammation in this setting remain incompletely understood but...

Cytotoxic chemotherapy is the standard of care for patients with triple negative breast cancer (TNBC). Most patients with advanced TNBC progress after chemotherapy and die from metastatic disease. Currently, no established targeted therapeutics or biomarkers of outcome/response have been clinically approved in the context of TNBC. The aggressive na...

Invasive lobular carcinoma (ILC) is a subtype of breast cancer comprising 10% of breast tumours. ILC is characterised by a loss of E-cadherin, and is generally estrogen receptor (ER) positive. The majority of ILC breast cancers are treated with endocrine therapy, although approximately one in three women are de novo resistant to therapy. To identif...

Specific MCL-1 inhibitor kills multiple myeloma and acute myeloid leukemia cells.

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apopt...

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. We analyzed pre-treatment T-ALL clinical...

RB1 loss of function in small cell lung cancer causes dependency on Aurora kinases for survival, which can be targeted therapeutically.

Targeting leukemia regenerating cells following chemotherapy can prevent relapse of the disease.

Patient-derived organoids in pancreatic cancer maintain genotypic, transcriptomic, and potentially phenotypic responses to chemotherapy of the primary tumor. One of the diculties in cancer biology is that the model systems we use for research do not accurately represent the complexity and heterogeneity of the primary tumor. The current state-of-the...

Melanoma can be clustered into four differentiation states, with the undifferentiated state being sensitive to ferroptosis. The epigenetic landscape helps deine the phenotype of the cell. Previously, a differentiating cell was considered as moving down through the rolling hills of the epigenetic landscape to settle in a valley as a differentiated c...

Combining BCL-2 inhibitor venetoclax with monoclonal CD20 antibody rituximab greatly enhances progression-free survival compared with bendamustine-rituximab in a phase 3 trial of relapsed or refractory chronic lymphocytic leukemia patients.

Invasive lobular carcinoma (ILC) is the second most common type of breast cancer after invasive ductal carcinoma (IDC), accounting for approximately 10-15% of all breast tumors. ILC is characterized by inactivation of E-Cadherin and neoplastic cells that invade the stroma in a "single-file" pattern. Women with ILC are usually older, have used hormo...

Approximately 70% of breast cancers overexpress the estrogen receptor α (ERα) and depend on this key transcriptional regulator for growth and differentiation. The discovery of novel mechanisms controlling ERα function represent major advances in our understanding of breast cancer progression and potentially offer attractive new therapeutic opportun...

Chromosomal instability produces cytosolic micronuclei that rupture and activate a viral response pathway, driving metastasis.

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of the outcome of cytotoxic chemotherapy for cancer. To fully exploit this finding, it will be important to understand the molecular genetic contexts responsible for the relative mitochondrial priming of chemotherapy...

Invasive lobular carcinoma (ILC) is a breast cancer subtype comprising 10% of breast tumors. The majority of ILC (90%) are estrogen receptor (ER)-positive and therefore candidates for endocrine therapy. Unfortunately, de novo resistant to endocrine therapies occurs in 33% of women and a further 40% will relapse on treatment. Therefore, novel therap...

Triple negative breast cancer (TNBC) lacks expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2). Importantly, there have been fewer advances in the treatment of TNBC with the mainstay of treatment being cytotoxic chemotherapy. All too often though tumor responds poorly to chemotherapy, or rela...

Approximately 70% of breast cancers overexpress the estrogen receptor α (ERα) and depend on this key transcriptional regulator for growth and differentiation. The discovery of novel mechanisms controlling ERα function represent major advances in our understanding of breast cancer progression and potentially offer attractive new therapeutic opportun...

Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell cycle-related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly availa...

The addition of ubiquitin to a target protein has long been implicated in the process of degradation and is the primary mediator of protein turnover in the cell. Recently, however, many non-proteolytic functions of ubiquitination have emerged as key regulators of cellular homeostasis. In this review, we will describe the various non-traditional fun...

Invasive lobular carcinoma (ILC) is the second most common type of breast cancer after invasive ductal carcinoma (IDC), accounting for approximately 10-15% of all breast tumors. ILC is characterized by inactivation of E-Cadherin and neoplastic cells that invade the stroma in a "single-file" pattern. Women with ILC are usually older, have used hormo...

Although contemporary combination chemotherapy can cure a substantial fraction of patients with T-cell acute lymphoblastic leukemia (T-ALL), front-line therapy fails in 15-20% of children and 50-70% of adults, and these patients have a poor prognosis. Strikingly, half of treatment failure events in childhood T-ALL are induction failure, suggesting...

Insights distilled from integrating multiple big-data or “omic” datasets have revealed functional hierarchies of molecular networks driving tumorigenesis and modifiers of treatment response. Identifying these novel key regulatory and dysregulated elements is now informing personalized medicine. Crucially, although there are many advantages to this...

Supplementary Data Legend: Se, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value. For the t(11;14) translocation test, a positive test was determined by the presence of the translocation. For the BH3 profiling test, a positive test was defined by a BAD (100 µM) response (% cytochrome c negative cells) > 50...

Breast cancer is the most common cancer in women and great advancements have been made for individualised patient treatment. Through understanding the underlying altered biology in the different subtypes of breast cancer, targeted therapeutics have been developed. Unfortunately, resistance to targeted therapy, intrinsic or acquired, is a recurring...

Triple-negative breast cancer (TNBC) is defined by absent expression of estrogen receptor (ER), progesterone receptor (PR) and non-overexpression of human epidermal growth factor receptor 2 (HER2), representing a heterogeneous subgroup of breast cancer with substantial genotypic and phenotypic diversity. TNBC patients commonly exhibit poor prognosi...

Triple-negative breast cancer (TNBC) represents a heterogeneous subgroup of breast cancer with substantial genotypic and phenotypic diversity. TNBC patients commonly exhibit poor prognosis and high relapse rates at early stages after conventional treatments. Currently, there is a lack of biomarkers and targeted therapies for the management of TNBC....

Targeted therapies designed to exploit specific molecular pathways in aggressive cancers are an exciting area of current research. Mixed Lineage Leukemia (MLL) mutations such as the t(4;11) translocation cause aggressive leukemias that are refractory to conventional treatment. The t(4;11) translocation produces an MLL/AF4 fusion protein that activa...

Document S1. Supplemental Experimental Procedures, Figures S1–S6, and Tables S1–S4

s: AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; September 20-23, 2014; Philadelphia, PA Most biomarkers in cancer rely on the study of parts of dead cells: DNA, RNA, or proteins. Studying viable functioning cells offers the opportunity to capture some of the complexity that is lost upon killing t...

Despite recent therapeutic advances that have doubled the median survival time of patients with multiple myeloma (MM), intratumor genetic heterogeneity contributes to disease progression and emergence of drug resistance. MicroRNAs (miRs), are noncoding small RNAs that play important roles in the regulation of gene expression, and have been implicat...

Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.

Despite significant improvement in the treatment of Multiple Myeloma (MM), patients still experience relapse and the disease remains incurable. Cellular fate decision in response to drug therapy is mainly determined by the interactions among BCL-2 family members. Thus anti-apoptotic BCL-2 family proteins represent an attractive target for therapy....

Hypodiploid Acute Lymphoblastic Leukemia (ALL), is a high-risk subtype of ALL characterized by multiple chromosomal losses with an event-free survival <40%. Hypodiploidy remains an independent marker of poor outcome. In particular, outcomes for the two subtypes: low hypodiploid (32-39 chromosomes) and near haploid (24-31 chromosomes) ALL have not i...

Many, if not most, anti-cancer agents kill cancer cells via the mitochondrial pathway of apoptosis. We have investigated ways that we can predict whether a particular agent will active apoptotic signaling on a personalized basis. We have found that we can predict response to conventional chemotherapy and to BCL-2 inhibition based on BH3 Profiling....

PURPOSE: Predictive biomarkers are required to identify patients who may benefit from the use of BH3 mimetics such as ABT-263. This study investigated the efficacy of ABT-263 against a panel of patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts and utilized cell and molecular approaches to identify biomarkers that predict in vi...

Nearly all attempts to understand and predict response of patient cancer cells to therapeutics rely on measurements of static properties at a single time point such as protein abundance, gene expression profiling, or genetic code. While these approaches have doubtless yielded useful information to guide therapy, it is often the case that observing...

Many, perhaps most, cancer chemotherapy agents kill cancer cells via the mitochondrial pathway of apoptosis that is controlled by the Bcl-2 family of proteins. Bcl-2 family proteins regulate commitment to cell death by controlling mitochondrial outer membrane permeabilization (MOMP). To better understand how cancer cells commit to apoptosis, and wh...

Mitochondria are cellular organelles that regulate commitment to and execution of apoptosis. The intrinsic apoptotic pathway culminates in the permeabilization of the mitochondrial outer membrane and dismantling of the cell. Apoptosis of cancer cells is a favorable outcome when administering chemotherapeutic treatment, yet the basis for why some ca...

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Successful treatment of most human cancers is dependent on tumor cell sensitivity to chemotherapy yet the basis for chemosensitivity is poorly understood. We have previously shown that a cancer's proximity to the apoptotic threshold, a property we call "apoptotic priming,"...

Much deliberation surrounds how the two homeostatic pathways, autophagy and apoptosis, converge; in the December 9 issue of Molecular Cell, Rubinstein et al. (2011) identify a proapoptotic role for the autophagic protein Atg12, based on a BH3-like domain, which enables binding and inhibition of antiapoptotic Bcl-2 family proteins.

1442 Cytotoxic chemotherapy, still a mainstay of current cancer treatment, targets ubiquitous elements such as DNA and microtubules. Despite decades of clinical use of chemotherapy, determinants of response to such treatments are poorly understood. Here, we showed that clinical response to cytotoxic agents is largely regulated by the initial proxim...

Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in the pathogenesis of MM and in the development of drug resistance by MM cells. Selectins are involved in extravasation and homing of leukocytes to target organs. In the present study, we focused on adhesion dynamics that involve P-selectin glycoprote...

Cancer cells show deviant behavior that induces apoptotic signaling. To survive, cancer cells typically acquire changes enabling evasion of death signals. One way they do this is by increasing the expression of anti-apoptotic BCL-2 proteins. Anti-apoptotic BCL-2 family proteins antagonize death signaling by forming heterodimers with pro-death prote...

The endoplasmic reticulum (ER) is the main site for protein folding, lipid biosynthesis, and calcium storage in the cell. Disturbances of these critical cellular functions lead to ER stress. The ER responds to disturbances in its homeostasis by launching an adaptive signal transduction pathway, known as the unfolded protein response (UPR). The UPR...

Hypoxia and doxorubicin can cause cardiotoxicity and loss of myocardial function. These effects are due, in part, to an induction of apoptosis. Herein we identify the apoptotic pathways activated in H9c2 cells in response to hypoxia (O(2)/N(2)/CO(2), 0.5:94.5:5) and doxorubicin (0.5 muM). Although the apoptosis induced was accompanied by induction...

The glucocorticoid dexamethasone (Dex) has been reported to modulate a number of signaling pathways and physiological processes, including apoptosis. This study was carried out to investigate the cytoprotective mechanism of Dex in C6 glioma cells. Pre-treatment of cells with Dex inhibited apoptosis induced by staurosporine, etoposide and thapsigarg...