Liver Toxicity halts Clinical Trial of IAP Antagonist for Advanced Solid Tumors
Writer/Curator Stephen J. Williams, Ph.D.
A recent press release on FierceBiotech reported the FDA had put a halt on a phase 1 study for advanced refractory solid tumors and lymphomas of Curis Inc. oral inhibitor of apoptosis (IAP) antagonist CUDC-427. The FDA placed the trial on partial clinical hold following reports of a death of a patient from severe liver failure. The single-agent, dose escalation Phase 1 study was designed to determine the maximum tolerated dose and recommended doses for a Phase 2 trial. The press release can be found at:
http://www.fiercebiotech.com/press-releases/curis-reports-third-quarter-2013-financial-results-and-provides-cudc-427-de.
According to the report one patient with breast cancer that had metastasized to liver, lungs, bone, and ovaries developed severe hepatotoxicity as evidenced by elevated serum transaminase activities (AST and ALT) and hyper-billirubinemia. Serum liver enzyme activities did not attenuate upon discontinuation of CUDC-427. This was unlike prior experience to the CUDC-427 drug, in which decreased hepatic function was reversed upon drug discontinuation. The patient died from liver failure one month after discontinuation of CUDC-427.
It was noted that no other patient had experienced such a serious, irreversible liver dysfunction.
Although any incidence of hepatotoxicity can be cause for concern, the incidence of IDIOSYNCRATIC IRREVERSIBLE HEPATOTOXICITY warrants a higher scrutiny.
Four general concepts can explain toxicity profiles and divergences between individuals:
- Toxicogenomics: Small differences in the genetic makeup between individuals (such as polymorphisms (SNP) could result in differences in toxicity profile for a drug. This ais a serious possibility as only one patient presented with such irreversible liver damage
- Toxicodynamics: The toxicologic effect is an extension of the pharmacologic mechanism of action (or lack thereof: could there have been alternate signaling pathways activated in this patient or noncanonical mechanism)
- Toxicokinetic: The differences in toxicological response due to differences in absorption, distribution, metabolism, excretion etc. (kinetic parameters)
- Idiosyncratic: etiology is unknown; usually a minority of adverse effects
Since there is not enough information to investigate toxicogenomic or toxicokinetic mechanisms for this compound, the rest of this post will investigate the possible mechanisms of hepatotoxicity due to IAP antagonists and clues from other clinical trials which might shed light on a mechanism of toxicity (toxicodynamic) or idiosyncratic events.
Therefore this post curates the current understanding of drug-induced liver injury (DILI), especially focusing on a type of liver injury referred to as idiosyncratic drug-induced liver injury (IDILI) in the context of:
- Targeted and newer chemotherapies such as IAP antagonists
- Current concepts of mechanisms of IDILI including:
i) Inflammatory responses provoked by presence of disease
ii) Cellular stresses, provoked by disease, uncovering NONCANONICAL toxicity pathways
iii) Pharmacogenomics risk factors of IDILI
Eventually this post aims to stimulate the discussion:
- Given inflammation, genetic risk factors, and cellular stresses (seen in clinical setting) have been implicated in idiosyncratic drug-induced liver injury from targeted therapies, should preclinical hepatotoxicity studies also be conducted in the presence of the metastatic disease?
- Does inflammation and cellular stress from clinical disease unmask NONCANONICAL pharmacologic and/or toxicological mechanisms of action?
Classification of types of Cellular Liver injury: A listing of types of cellular injury is given for review
I. Hepatic damage after Acute Exposure
A. Cytotoxic (Necrotic): irreversible cell death characterized by loss of cell membrane integrity, intracellular swelling, nuclear shrinkage (pyknosis) and eventual cytoplasmic breakdown of nuclear DNA (either by a process known as karyolysis or karyorhexus) localized inflammation as a result of release of cellular constituents. Intracellular ATP levels are commonly seen in necrotic death. Necrosis, unlike apoptosis, does not require a source of ATP. A nice review by Yoshihide Tsujimoto describing and showing (by microscopy) the differences between apoptosis and necrosis can be found here.
B. Cholestatic: hepatobiliary dysfunction with bile stasis and accumulation of bile salts. Cholestatic injury can result in lipid (particularly cholesterol) accumulation in cannicular membranes resulting in decreased permeability of the membrane, hyperbillirubinemia and is generally thought to result in metabolic defects.
C. Lipid Peroxidation: free radical generation producing peroxide of cellular lipids, generally resulting in a cytotoxic cell death
II. Hepatic damage after Chronic Exposure
A. Chirrotic: Chronic morphologic alteration of the liver characterized by the presence of septae of collagen distributed throughout the major portion of the liver; Forms fibrous sheaths altering hepatic blood flow, resulting in a necrotic process with scar tissue; Alteration of hepatic metabolic systems.
B. Carcinogenesis
III. Idiosyncratic Drug Induced Liver Injury
The aforementioned mechanisms of hepatotoxicity are commonly referred to as the “intrinsic” (or end target-organ) toxicity mechanisms. Idiosyncratic drug-induced liver injury (IDILI) is not well understood but can be separated into allergic and nonallergic reactions. Although the risk of acute liver failure associated with idiosyncratic hepatotoxins is low (about 1 in ten thousand patients) there are more than 1,000 drugs and herbal products associated with this type of toxic reaction. Idiosyncratic drug induced liver failure usually gets a black box warning from the FDA. Idiosyncratic drug-induced liver injury differs from “intrinsic” toxicity in that IDILI:
- Happens in a minority of patients (susceptible patients)
- Not reproducible in animal models
- Not dose-dependent
- Variable time of onset
- Variable liver pathology (not distinctive lesions)
- Not related to drug’s pharmacologic mechanism of action (trovafloxacin IDILI vs. levofloxacin)
A great review in Perspectives in Pharmacology written by Robert Roth and Patricia Ganey at Michigan State University explains these differences between intrinsic and idiosyncratic drug-induced hepatotoxicity[1] (however authors do note that there are many similarities between the two mechanisms). It is felt that drug sensitivity (allergic) and inflammatory responses (nonallergic) may contribute to the occurrence of IDILI. For instance lipopolysaccharide (LPS) form bacteria can potentiate acetaminophen toxicity. In fact animal models of IDILI have been somewhat successful:
- co-treatment of rats and mice with nontoxic doses of trovafloxacin (casues IDILI in humans) and LPS resulted in marked hepatotoxicity while no hepatotoxicity seen with levofloxacin plus LPS[2]
- correlates well with incidence of human IDILI (adapted from a review Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models (in Pharmacology Reviews)[3]. Idiosyncratic injury damage has been reported for diclofenac, halothane, and sulinac. These drugs also show hepatotoxicity in the LPS model for IDILI.
- Roth and Ganey suggest the reason why idiosyncratic hepatotoxicity is not seen in most acute animal toxicity studies is that, in absence of stress/inflammation IDILI occurrence is masked by lethality but stress/inflammation shifts increases sensitivity to liver injury at a point before lethality is seen
Figure. Idiosyncratic toxic responses of the liver. In the absence of stress and/or genetic factors, drug exposure may result in an idiosyncratic liver injury (IDILI) at a point (or dose) beyond the therapeutic range and lethal exposure for that drug. Preclinical studies, usually conducted at sublethal doses, would not detect DILI . Stress and/or genetic factors sensitize the liver to toxic effects of the drug (synergism) and DILI is detected at exposure levels closer to therapeutic range. Note IDILI is not necessarily dose-dependent but cellular stress (like ROS or inflammation) may expose NONCANONICAL mechanisms of drug action or toxicity which result in IDILI. Model adapted from Roth and Ganey.
What Stress factors contribute to IDILI?
Various stresses including inflammation from bacterial, viral infections ,inflammatory cytokines and stress from reactive oxygen (ROS) have been suggested as mechanisms for IDILI.
- Inflammation/Cytokines (also discussed in other sections of this post): Inflammation has long been associated with human cases of DILI. Many cytokines and inflammatory mediators have been implicated including TNFα, IL7, TGFβ, and IFNϒ (viral infection) leading some to conclude that serum measurement of cytokines could be a potential biomarker for DILI[4]. In addition, ROS (see below) is generated from inflammation and also considered a risk factor for DILI[5].
- Reactive Oxygen (ROS)/Reactive Metabolites: Oxidative stress, either generated from reactive drug metabolites or from mitochondrial sources, has been shown to be involved in apoptotic and necrotic cell death. Both alterations in the enzymes involved in the generation of and protection from ROS have been implicated in increased risk to DILI including (as discussed further) alterations in mitochondrial superoxide dismutase 2 (SOD2) and glutathione S-transferases. Both ROS and inflammatory cytokines can promote JNK signaling, which has been implicated in DILI[6].
Dr. Neil Kaplowitz suggested that we:
“develop a unifying hypothesis that involves underlying genetic or acquired mitochondrial abnormalities as a major determinant of susceptibility for a number of drugs that target mitochondria and cause DILI. The mitochondrial hypothesis, implying gradually accumulating and initially silent mitochondrial injury in heteroplasmic cells which reaches a critical threshold and abruptly triggers liver injury, is consistent with the findings that typically idiosyncratic DILI is delayed (by weeks or months), that increasing age and female gender are risk factors and that these drugs are targeted to the liver and clearly exhibit a mitochondrial hazard in vitro and in vivo. New animal models (e.g., the Sod2(+/-) mouse) provide supporting evidence for this concept. However, genetic analyses of DILI patient samples are needed to ultimately provide the proof-of-concept”[7].
Figures. Mechanisms of Drug-Induced Liver Injury and Factors related to the occurrence of DILI (used with permission from Oxford Press; reference [7])
To this end, Dr. Brett Howell and other colleagues at the Hamner-UNC Institute for Drug Safety Sciences (IDSS) developed an in-silico model of DILI ( the DILISym™ model)which is based on depletion of cellular ATP and reactive metabolite formation as indices of DILI.
Have there been Genetic Risk Factors identified for DILI?
Candidate-gene-associated studies (CGAS) have been able to identify several genetic risk factors for DILI including:
- Uridine Diphosphate Glucuronosyltransferase 2B7 (UGT2B7): variant increased susceptibility to diclofenac-induced DILI
- Adenosine triphosphate-binding cassette C2 (ABCC2) variant ABCC-24CT increased susceptibility to diclofenac-induced DILI
- Glutathione S-transferase (GSTT1): patients with a double GSTT1-GSTM1 null genotype had a significant 2.7 fold increased risk of DILI from nonsteroidal anti-inlammatory agents, troglitazone and tacrine. GSTs are involved in the detoxification of phase 1 metabolites and also protect against cellular ROS.
Although these CGAS confirmed these genetic risk factors, Stefan Russman suggests a priori genome-wide association studies (GWAS) might provide a more complete picture of genetic risk factors for DILI as CGAS is limited due to
- Candidate genes are selected based on current mechanisms and knowledge of DILI so genetic variants with no known knowledge of or mechanistic information would not be detected
- Many CGAS rely on analysis of a limited number of SNP and did not consider intronic regions which may control gene expression
A priori GWAS have the advantage of being hypothesis-free, and although they may produce a high number of false-positives, new studies of genetic risk factors of ximelagatran, flucioxaciliin and diclofenac-induced liver injury are using a hybrid approach which combines the whole genome and unbiased benefits of GWAS with the confirmatory and rational design of CGAS[8-10].
Even though idiosyncratic DILI is rare, the severity, unpredictable onset, and unknown etiology and risk factors have prompted investigators such as Stefan Russmann from University Hospital Zurich and Ignazio Grattagliano from University of Bari to suggest:
Identification of risk factors for rare idiosyncratic hepatotoxicity requires special networks that contribute to data collection and subsequent identification of environmental as well as genetic risk factors for clinical cases of idiosyncratic DILI[11].
Therefore, a DILI network project (DILIN) had been developed to collect samples and detailed genetic and clinical data on IDILI cases from multiple medical centers. The project aims to identify the upstream and downstream genetic risk factors for IDILI[12]. Please see a SlideShare presentation here of the goals of the DILI network project.
Drs Colin Spraggs and Christine Hunt had reviewed possible genetic risk factors of DILI seen with various tyrosine kinase inhibitors (TKIs) including Lapatinib (Tykerb/Tyverb©, a dual inhibitor of HER2/EGFR heterodimer) and paopanib (Votrient©; a TKI that targets VEGFR1,2,3 and PDGFRs)[13].
From a compilation of studies:
- Elevation in serum bilirubin during treatment with lapatinib and pazopanib are associated with UGT1A1 polymorphism related to Gilbert’s syndrome (a clinically benign syndrome)
- Anecdotal evidence shows that polymorphisms of lapatinib and pazopanib metabolizing enzymes may contribute to differences seen in onset of DILI
- Pazopanib-induced elevations of ALT correlate with HFE variants, suggesting alterations in iron transport may predispose to DILI
- Strong correlations between lapatinib-induced DILI and class II HLA locus suggest inflammatory stress response important in DILI
Note that these clinical findings were not evident from the preclinical tox studies. According to the European Medicines Agency assessment report for Tykerb states: “the major findings in repeat dose toxicity studies were attributed to lapatinib pharmacology (epithelial effect in skin and GI system. The toxic events occurred at exposures close to the human exposure at the recommended dose. Repeat-dose toxicity studies did not reveal important safety concerns than what would be expected from the mode of action”.
However, it should be noted that in high dose repeat studies in mice and rats, severe lethality was seen with hematologic, gastrointestinal toxicities in combination with altered blood chemistry parameters and yellowing of internal organs.
IAP Antagonists, Mechanism of Action, and Clinical Trials:
A few IAP antagonists which are in early stage development include:
- Norvatis IAP Inhibitor LCL161: at 2012 San Antonia Breast Cancer Symposium, a phase 1 trial in triple negative breast cancer showed promising results when given in combination with paclitaxel.
- Ascenta Therapeutics IAP inhibitor AT-406 in phase 1 in collaboration with Debiopharm S.A. showed antitumor efficacy in xenograft models of breast, pancreatic, prostate and lung cancer. The development of this compound is described in a paper by Cai et. al.
National Cancer Institute sponsored trials using antagonists of IAPs include
- Phase II Study of Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer (NCI-12-C-0191). Principle Investigator: Dr. Christina Annunziata. See the protocol summary. More open trials for this drug are located here. Closed trials including safety studies can be found here.
- A Phase 1 non-randomized dose escalation study to determine maximum tolerated dose (MTD) and characterize the safety for the TetraLogic compound TL32711 had just been completed. Results have not been published yet.
- Closed Clinical trials with the IAP antagonist HGS1029 in advanced solid tumors determined that weekly i.v. administration of HGS1029 reported a safety issue for primary outcome measures
A great review on IAP proteins and their role as regulators of apoptosis and potential targets for cancer therapy [14] can be found as a part of a Special Issue in Experimental Oncology “Apoptosis: Four Decades Later”. Human IAPs (inhibitors of apoptosis) consist of eight proteins involved in cell death, immunity, inflammation, cell cycle, and migration including:
In general, IAP proteins are directly involved in inhibiting apoptosis by binding and directly inhibiting the effector cysteine protease caspases (caspase 3/7) ultimately responsible for the apoptotic process [15]. IAPs were actually first identified in baculoviral genomes because of their ability to suppress host-cell death responses during viral infection [16]. IAP proteins are often overexpressed in cancers [17].
Apoptosis is separated into two pathways, defined by the initial stress or death signal and the caspases involved:
- Extrinsic pathway: initiated by TNFα and death ligand FasLigand; involves caspase-8; process inhibited by IAP1/2
- Intrinsic pathway: initiated by DNA damage, irradiation, chemotherapeutics; mitochondrial pathway involving caspase 9 and cytochrome c release from mitochondria; mitochondria also releases SMAC/DIABLO, which binds and inhibits XIAP (XIAP inhibits the Intrinsic apoptotic pathway.
Intrinsic and Extrinsic pathways of apoptosis. Figure photocredit (wikidot.com)
The Curis IAP antagonist (and others) is a SMAC small molecule mimetic. It is interesting to note [18, 19] that IAP antagonists can result in death by
- Apoptosis: an IAP antagonist in presence of competent TNFα signaling
- Necrosis: seen with IAP inhibitors in cells with altered TNFα signaling or with presence of caspase inhibitors
IAPs are also involved in the regulation of signaling pathways such as:
NF-ΚB signaling pathway
NF-ΚB is a “rapid-acting” transcription factor which has been found to be overexpressed in various cancers. Under most circumstances NF-ΚB translocation to the nucleus results in transcription of genes related to cell proliferation and survival. NF-ΚB signaling is broken down in two pathways
- Canonical: Canonical pathway can be initiated (for example in inflammation) when TNF-α binds its receptors activating death domains (TRADD)
- Noncanonical: since requires new protein synthesis takes longer than canonical signaling. Can be initiated by other TNF like ligands like CD40
IAP1/2 is a negative regulator of the noncanonical NF-ΚB signaling pathway by promoting proteosomal degradation of the TRAF signaling complex. A wonderfully annotated list of NF-ΚB target genes can be found on the Thomas Gilmore lab site at Boston University at http://www.bu.edu/nf-kb/gene-resources/target-genes/ .
NF-ΚB has been considered a possible target for chemotherapeutic development however Drs. Veronique Baud and Michael Karin have pondered the utility of IAP antagonists as a good target in their review: Is NF-ΚB a good target for cancer therapy?: Hopes and pitfalls [20]. The authors discuss issues such that IAP antagonism induced both the classical and noncanonical NF-ΚB pathway thru NIK stabilization, resulting in stabilization of NF-ΚB signaling and thereby undoing any chemotherapeutic effect which would be desired.
AKT signaling
IAPs have been shown to interact with other proteins including a report that SIAP regulates AKT activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian cancer cells and could be another mechanism involved in cisplatin resistance[21]. In addition there have been reports that IAPs can regulate JNK and MAPK signaling.
Therefore, IAPs are involved in CANONICAL and NONCANONICAL pathways.
IAPs can Regulate Pro-Inflammatory Cytokines
A recent 2013 JBC paper [22]showed that IAPs and their antagonists can regulate spontaneous and TNF-induced proinflammatory cytokine and chemokine production and release
- IAP required for production of multiple TNF-induced proinflammatory mediators
- IAP antagonism decreased TNF-mediated production of chemokines and cytokines
- But increased spontaneous release of chemokines
In addition Rume Damgaard and Mads Gynd-Hansen have suggested that IAP antagonists may be useful in treating inflammatory diseases like Crohn’s disease as IAPs regulate innate and acquired immune responses[23].
Toxicity profiles of IAP antagonists
NOTE: In a paper in Toxicological Science from 2012[24], Rebecca Ida Erickson form Genentech reported on the toxicity profile of the IAP antagonist GDC-0152 from a study performed in dogs and rats. A dose-dependent toxicity profile from i.v. administration was consistent with TNFα-mediated toxicity with
- Elevated plasma cytokines and an inflammatory leukogram
- Increased serum transaminases
- Inflammatory infiltrate and apoptosis/necrosis in multiple tissues
In a related note, a similar type of fatal idiosyncratic hepatotoxicity was reported in a 62 year-old man treated with the Raf kinase inhibitor sorafenib for renal cell carcinoma[25]: Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma; Case Report in BMC Cancer.
At week four after initiation of sorafenib treatment, the patient noticed increasing fatigue, malaise, gastrointestinal discomfort and abdominal rash. Although treatment was discontinued, jaundice developed and blood test revealed an acute hepatitis with
- Elevated serum ALT
- Elevated serum alkaline phosphatase
- Increased prothrombin time
- Increased LDH
…elevated levels seen in the case with the aforementioned IAP antagonist. Autopsy revealed
- Lobular hepatitis
- Mononuclear cell infiltrate
- Hepatocyte necrosis
These findings are in line with a drug-induced inflammation and IDILI. In addition to hepatotoxicity, renal insufficiency developed in this patient. The authors had suggested the death was probably due to “an idiosyncratic allergic reaction to sorafenib manifesting as hepatotoxicity with associated renal impairment”. The authors also noted that genome wide association studies of idiosyncratic drug-induced liver injury support involvement of major histocompatibility complex (MHC) polymorphisms[26]. MHC involvement has also been associated with lapatanib and pazopanib hepatotoxicity [27, 28].
Curis has been involved in another novel oncology therapeutic, a first in class.
Last year Roche and Genentech had won approval for a Hedgehog pathway inhibitor vismodegib for treatment of advanced basal cell carcinoma (reported at FierceBiotech©). Vismodegib was initially developed in collaboration with Curis, Inc. The hedgehog signaling pathway, which controls the function of Gli factors (involved in stem cell differentiation), is overactive in advanced basal cell carcinoma as well as other cancer types.
As an additional reference, the FDA National Center for Toxicological Research has developed THE LIVER TOXICITY KNOWLEDGE BASE (LTKB).
“The LTKB is a project designed to study drug-induced liver injury (DILI). Liver toxicity is the most common cause for the discontinuation of clinical trials on a drug, as well as the most common reason for an approved drug’s withdrawal from the marketplace. Because of this, DILI has been identified by the FDA’s Critical Path Initiatives as a key area of focus in a concerted effort to broaden the agency’s knowledge for better evaluation tools and safety biomarkers.”
A nice SlideShow of Toxicity of Targeted Therapies can be found here: http://www.slideshare.net/RashaHaggag/toxicities-of-targeted-therapies
Also please note that ALL GENES in this article are linked to their GENECARD
REFERENCES
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22. Kearney CJ, Sheridan C, Cullen SP, Tynan GA, Logue SE, Afonina IS, Vucic D, Lavelle EC, Martin SJ: Inhibitor of apoptosis proteins (IAPs) and their antagonists regulate spontaneous and tumor necrosis factor (TNF)-induced proinflammatory cytokine and chemokine production. The Journal of biological chemistry 2013, 288(7):4878-4890.
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24. Erickson RI, Tarrant J, Cain G, Lewin-Koh SC, Dybdal N, Wong H, Blackwood E, West K, Steigerwalt R, Mamounas M et al: Toxicity profile of small-molecule IAP antagonist GDC-0152 is linked to TNF-alpha pharmacology. Toxicological sciences : an official journal of the Society of Toxicology 2013, 131(1):247-258.
25. Fairfax BP, Pratap S, Roberts IS, Collier J, Kaplan R, Meade AM, Ritchie AW, Eisen T, Macaulay VM, Protheroe A: Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma. BMC cancer 2012, 12:590.
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28. Xu CF, Reck BH, Goodman VL, Xue Z, Huang L, Barnes MR, Koshy B, Spraggs CF, Mooser VE, Cardon LR et al: Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma. Journal of hepatology 2011, 54(6):1237-1243.
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