Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer

Whalen, Kerry A.; White, Brian H.; Quinn, James A.; Kriksciukaite, Kristina; Alargova, Rossitza; Yeung, Tsun P. Au; Bazinet, Patrick; Brockman, Adam; DuPont, Michelle M.; Oller, Haley; Gifford, James; Lemelin, Charles-Andre; Soo, Patrick Lim; Perino, Samantha; Moreau, Benoît; Shinde, Rajesh; Sweryda-Krawiec, Beata; Bilodeau, Mark T.; Wooster, Richard

doi:10.1158/1535-7163.mct-19-0022

Cited by 41 publications

(29 citation statements)

References 33 publications

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“…SSTR2A and SSTR5 tissue distribution was also assessed, revealing a prevalence of SSTR2A in pure LCNECs, a finding that should be connected with innovative data obtained with multiple SCLC models [48, 49], and that could be reproduced also for LCNEC. Interestingly, correlations between molecular alterations, Ki-67 subclasses A and B, and pure or combined histological types in our work reveal that pure LCNECs with either co-mutation of TP53 and RB1 , or with mutation of TP53 and absence of RB1 immunolabelling, demonstrate characteristics of SCLC-like LCNEC.…”

Section: Discussionmentioning

confidence: 70%

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis

et al. 2020

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Background: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. Methods: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. Results: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). Conclusions: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.

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Section: Discussionmentioning

confidence: 70%

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis

et al. 2020

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“…PEN-221 is a SST2 receptor subtype drug for the treatment of small cell lung cancer and neuroendocrine tumors in a Phase I/IIa clinical trial. Complete tumor regression has been achieved with repeated administration of low-dose PEN-221 or a single injection of high-dose PEN-221 [33].…”

Section: Targeting Integrinsmentioning

confidence: 99%

Peptide–drug conjugate-based novel molecular drug delivery system in cancer

Zhu

Tang

2021

Trends in Pharmacological Sciences

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Drug delivery systems are generally believed to comprise drugs and excipients. A peptide-drug conjugate is a single molecule that can simultaneously play multiple roles in a drug delivery system, such as in vivo drug distribution, targeted release, and bioactivity functions. This molecule can be regarded as an integrated drug delivery system, so it is called a molecular drug delivery system. In the context of cancer therapy, a peptide-drug conjugate comprises a tumor-targeting peptide, a payload, and a linker. Tumor-targeting peptides specifically identify membrane receptors on tumor cells, improve drug-targeted therapeutic effects, and reduce toxic and side effects. Payloads with bioactive functions connect to tumor-targeting peptides through linkers. In this review, we explored ongoing clinical work on peptide-drug conjugates targeting various receptors. We discuss the binding mechanisms of tumor-targeting peptides and related receptors, as well as the limiting factors for peptide-drug conjugate-based molecular drug delivery systems. Towards enhanced targeting on tumorsDespite the rapid development of anticancer drugs in the past few decades, cancer is one of the leading causes of death in the world [1]. Due to the lack of an effective means to distinguish tumor cells from normal cells [2], the accumulation efficiency of anticancer drugs in tumor cells is low and the toxic side effects on normal tissues are high. In the treatment process, drug resistance problems are caused by tumor heterogeneity [3], drug inactivation, transport, and metabolism, changes in drug targets, and tumor microenvironment dysfunction [4]. Although advanced drug delivery methods can partially solve problems of targeting, toxicity, and drug resistance [5], difficult industrialization, complicated process control, and huge costs remain insurmountable obstacles.Peptide-drug conjugates are emerging molecular drug delivery system (see Glossary) that achieve precise drug delivery and tumor-targeted release at the molecular level [6]. Current drug delivery systems, such as nano-drug delivery systems, use various complex excipients to assemble nanoscale particles that encapsulate drugs to be passively or actively delivered to target organs. The anticancer efficacy of nano-drug delivery systems is improved by an enhanced permeability retention effect to increase drug accumulation in tumors and the toxicity of nanodrug delivery systems is reduced by the long systemic circulation to decrease drug accumulation in normal organs [7]. However, a reappraisal of nano-drug delivery system design is suggested to improve their clinical efficacy and safety in cancer patients [8].By contrast, molecular drug delivery systems use a single peptide-drug conjugate molecule to achieve in vivo drug delivery, targeted drug release, and bioactivity, which can maximize the targeting effect and reduce drug resistance. Peptide-drug conjugates, which were first reported in 1972 by Freer et al.[9] (Box 1), are similar to the tethering of ligand-targeted drugs [10],

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“…PEN-221 targets SSTR2-expressing cells, and based on anti-tumor activity in SSTR2-expressing NET xenografts was moved into the clinical arena. 74 An ongoing phase I/II clinical trial is testing PEN-221 in GEP NETs and small-cell lung cancer. The phase I results from this study were presented at ASCO 2018.…”

Section: Miscellaneous Agentsmentioning

confidence: 99%

Novel therapeutics for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors

Das

Dasari

2021

Ther Adv Med Oncol

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Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) represent the most common subtype of NETs. The incidence of all NETs, and specifically GEP NETs, has risen exponentially over the last three decades. Only within the past several years have these tumors been appropriately classified, allowing for meaningful drug development. Broadly, some of the most exciting drug classes being developed for patients with well-differentiated GEP NETs include newer types of peptide receptor radionuclide therapy (PRRT) or combinations which increase the potency of lutetium-177 (177Lu)-Dotatate, novel multi-target receptor tyrosine kinase inhibitors (RTKIs) and immunotherapy modalities, beyond checkpoint inhibitors, which seek to unleash the immune system against NETs. Specifically looking at newer types of PRRT, somatostatin receptor antagonists and alpha-emitter radionuclides each have demonstrated the ability to elicit greater DNA damage than 177Lu-Dotatate in preclinical models. Early clinical experiences with each of these agents suggest they may be more cytotoxic than 177Lu-Dotatate. Other approaches seeking to build upon the DNA damage created by 177Lu-Dotatate include combinations of PRRT with radiosensitizers such as heat shock protein 90 inhibitors, hedgehog inhibitors, chemotherapy combinations, and triapine. Many of these combinations have just begun to be tested clinically. With regards to novel RTKIs, some of the ones which have demonstrated potent cytoreductive potential include cabozantinib and lenvatinib. Other RTKIs which are further along the clinical development spectrum and have demonstrated benefit in randomized trials include surufatinib and pazopanib. And though single-agent immune checkpoint inhibitors have not demonstrated significant anti-tumor activity in patients with GEP NETs, outside of certain biomarker selected subsets, somatostatin receptor-directed chimeric antigen receptor (CAR) T cells and vaccines such as SurVaxM, which targets survivin, represent two means through which NET-directed immunity may be modulated. The potential of these agents, if clinically realized, will likely improve outcomes for patients with well-differentiated GEP NETs.

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Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer

Cited by 41 publications

References 33 publications

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis

Peptide–drug conjugate-based novel molecular drug delivery system in cancer

Novel therapeutics for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors

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