A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Panobinostat, an HDAC Inhibitor, Combined with Erlotinib in Patients with Advanced Aerodigestive Tract Tumors

Gray, Jhanelle E.; Haura, Eric B.; Chiappori, Alberto; Tanvetyanon, Tawee; Williams, Charles C.; Pinder-Schenck, Mary; Kish, Julie A.; Kreahling, Jenny; Lush, Richard M.; Neuger, Anthony; Tetteh, Leticia; Akar, Angela; Zhao, Xiuhua; Schell, Michael J.; Bepler, Gerold; Altiok, Soner

doi:10.1158/1078-0432.ccr-13-2235

Cited by 51 publications

(40 citation statements)

References 52 publications

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“…In a phase 1 study of erlotinib plus the HDAC inhibitor panobinostat, all documented radiographic responses occurred among EGFR -mutant, EGFR inhibitor-naïve patients. 36 In this trial, serum romidepsin concentrations achieved at all romidepsin dose levels well exceeded the IC50 of romidepsin against NSCLC cell lines in vitro (2.25 ng/mL). 16 Consistent with preclinical observations, 21 we observed potential clinical benefit in cases not typically considered responsive to EGFR inhibitors.…”

Section: Discussionmentioning

confidence: 64%

“…Among 10 patients evaluable for radiographic response, the disease control rate was 60%, which is comparable to other studies combining erlotinib and HDAC inhibitors. 36 To further place these results in context, it is important to consider that in this trial there were no identified cases with sensitizing EGFR mutations, all patients were current or former smokers, and all received prior treatment for their advanced NSCLC diagnosis. In addition, seven patients (41%) were previously treated with erlotinib before enrollment.…”

Section: Discussionmentioning

confidence: 99%

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Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer

et al. 2015

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Purpose Preclinical studies demonstrated anti-tumor efficacy of the combination of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in non-small cell lung cancer (NSCLC) models that were insensitive to erlotinib monotherapy. We therefore, studied this combination in a phase 1 clinical trial in previously treated advanced NSCLC. Methods Romidepsin (8 or 10 mg/m2) was administered intravenously on days 1, 8, and 15 every 28 days in combination with erlotinib (150 mg orally daily), with romidepsin monotherapy lead-in during Cycle 1. Correlative studies included peripheral blood mononuclear cell HDAC activity and histone acetylation status, and EGFR pathway activation status in skin biopsies. Results A total of 17 patients were enrolled. Median number of prior lines of therapy was 3 (range 1–5). No cases had a sensitizing EGFR mutation. The most common related adverse events were nausea, vomiting, and fatigue (each 82%), diarrhea (65%), anorexia (53%), and rash (41%). Dose-limiting nausea and vomiting occurred at the romidepsin 10 mg/m2 level despite aggressive antiemetic prophylaxis and treatment. Among 10 evaluable patients, the best response was stable disease (n = 7) and progressive disease (n = 3). Median progression-free survival (PFS) was 3.3 months (range 1.4–16.5 months). Prolonged PFS (>6 months) was noted in a KRAS mutant adenocarcinoma and a squamous cell cancer previously progressed on erlotinib monotherapy. Romidepsin monotherapy inhibited HDAC activity, increased histone acetylation status, and inhibited EGFR phosphorylation. Conclusions Romidepsin 8 mg/m2 plus erlotinib appears well tolerated, has evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer

et al. 2015

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“…50 In addition, histone deacetylase inhibitors have been shown to overcome EGFR TKI resistance linked to epigenetic changes and EMT state in vitro 87–89 ; however, the clinical data are limited so far. 90,91 …”

Section: Signals From the Microenvironmentmentioning

confidence: 99%

Primary Double-Strike Therapy for Cancers to Overcome EGFR Kinase Inhibitor Resistance: Proposal from the Bench

Suda

Bunn

Rivard

et al. 2017

Journal of Thoracic Oncology

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Diverse molecular mechanisms that confer acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancers with sensitive EGFR mutations have been reported. However, it is not realistic to analyze for all these mechanisms at the time of resistance in clinical practice and establish adequate treatment targeting these numerous resistance mechanisms. Therefore, we believe that we should move our research focus from the exploration of “established” diverse resistance mechanisms to the elucidation of molecular mechanisms that enable cancer cells to remain alive at the early phase of the treatment. Here in this review, we summarize up-to-date molecular mechanisms that maintain residual tumor cells against EGFR TKI monotherapy in lung cancers with EGFR mutations. We classified these mechanisms into three categories. The first is a pre-existing minor subpopulation with a resistance mechanism such as a pretreatment T790M mutation that can be detected by highly sensitivity methods. The second is the reversible drug-tolerant state that is often observed in cell line models and accounts for the lack of complete response and continued survival of cells exposed to EGFR TKIs in patients. And the last is the role of the microenvironment, including survival signaling from fibroblasts or dying cancer cells and the role of poor vascularization. Primary double-strike cancer therapy, or even initial multiple-strike therapy, to cancer cells that cotarget EGFR and survival mechanism(s) simultaneously would be a promising strategy to improve the outcomes of patients with EGFR mutations.

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“…Pretreatment with the HDAC inhibitor has been previously reported that reverses resistance to gefitinib in lung cancer cells by upregulating E‐cadherin . Moreover, clinical studies have investigated the safety and efficacy of panobinostat, and its combination with EGFR‐TKIs, such as erlotinib . However, the detail inhibitory mechanism of panobinostat on EGFR‐TKI resistance is not clear.…”

Section: Discussionmentioning

confidence: 99%

Panobinostat sensitizes KRAS‐mutant non‐small‐cell lung cancer to gefitinib by targeting TAZ

Lee

Chen

et al. 2017

Intl Journal of Cancer

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Mutation of KRAS in non-small-cell lung cancer (NSCLC) shows a poor response to epidermal growth factor receptor (EGFR) inhibitors and chemotherapy. Currently, there are no direct anti-KRAS therapies available. Thus, new strategies have emerged for targeting KRAS downstream signaling. Panobinostat is a clinically available histone deacetylase inhibitor for treating myelomas and also shows potentiality in NSCLC. However, the therapeutic efficacy of panobinostat against gefitinib-resistant NSCLC is unclear. In this study, we demonstrated that panobinostat overcame resistance to gefitinib in KRAS-mutant/EGFR-wild-type NSCLC. Combined panobinostat and gefitinib synergistically reduced tumor growth in vitro and in vivo. Mechanistically, we identified that panobinostat-but not gefitinib-inhibited TAZ transcription, and the combination of panobinostat and gefitinib synergistically downregulated TAZ and TAZ downstream targets, including EGFR and EGFR ligand. Inhibition of TAZ by panobinostat or short hairpin RNA sensitized KRAS-mutant/EGFR-wild-type NSCLC to gefitinib through abrogating AKT/mammalian target of rapamycin (mTOR) signaling. Clinically, TAZ was positively correlated with EGFR signaling, and coexpression of TAZ/EGFR conferred a poorer prognosis in lung cancer patients. Our findings identify that targeting TAZ-mediated compensatory mechanism is a novel therapeutic approach to overcome gefitinib resistance in KRAS-mutant/EGFR-wild-type NSCLC.Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancers and remains the leading cause of cancerrelated deaths worldwide. Molecular driver mutations such as KRAS and epidermal growth factor receptor (EGFR) play an important role in lung tumorigenesis, and is therefore could be an attractive target for personalized therapy. The EGFRtyrosine kinase inhibitors (EGFR-TKIs) have shown efficacy in NSCLC patients, especially those harboring activating mutations in the EGFR. 1 However, an acquired secondary mutation in the EGFR (T790M) or the somatic mutation in KRAS results in resistance to EGFR-TKIs. Moreover, KRAS mutations in EGFR-wild type NSCLC patients lost efficacy to EGFR-TKIs and front-line chemotherapy. 2,3 Thus, elucidating compensatory signaling would be a considerable approach to identify therapeutic targets and overcome the resistance.Histone deacetylase inhibitors (HDACis) are promising antitumor agents by globally attenuating acetylation events and blocking several cancer-related signaling pathways. Among these, panobinostat (LBH589) has been extensively studied against a wide variety of hematological and solid malignancies, and was approved for treating multiple myelomas in the clinic. 4 Panobinostat showed potentiality against several cancer types including NSCLC, 5-7 and increased efficacy when in combination with chemotherapy or radiotherapy

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A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Panobinostat, an HDAC Inhibitor, Combined with Erlotinib in Patients with Advanced Aerodigestive Tract Tumors

Cited by 51 publications

References 52 publications

Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer

Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer

Primary Double-Strike Therapy for Cancers to Overcome EGFR Kinase Inhibitor Resistance: Proposal from the Bench

Panobinostat sensitizes KRAS‐mutant non‐small‐cell lung cancer to gefitinib by targeting TAZ

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