Therapeutic Advances in Oncology
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International Journal of Molecular Sciences Review Therapeutic Advances in Oncology Jinsha Liu †, Priyanka Pandya † and Sepideh Afshar * Protein Engineering, Lilly Biotechnology Center, Eli Lilly and Company, San Diego, CA 92121, USA; [email protected] (J.L.); [email protected] (P.P.) * Correspondence: [email protected]; Tel.: +1-8586388585 † These authors contributed equally to this work. Abstract: Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma. Keywords: therapeutic modalities; innovation; oncology; breast cancer; lung cancer; multiple myeloma 1. Introduction More than 17 million new cancer cases have been reported worldwide in the past two years and the number is expected to grow to 27.5 million by 2040 [1]. Investment in early detection methods, awareness of carcinogens and, most importantly, the development of Citation: Liu, J.; Pandya, P.; Afshar, S. novel therapeutics has resulted in decreased mortality in cancer patients. Around 77 new Therapeutic Advances in Oncology. oncology therapeutics were approved in the last five years (Table S1), however, oncology Int. J. Mol. Sci. 2021, 22, 2008. still remains as one of the most challenging areas of drug discovery [2]. https://doi.org/10.3390/ijms22042008 1.1. Small Molecule Therapeutics Academic Editor: Dharmendra Small molecules remain the major therapeutic modalities for cancer treatment (Figure Kumar Yadav S1). Since 2015, 52 novel small molecule cancer drugs have been approved (Table1). To Received: 26 January 2021 increase specificity and potency, majority of these small molecules are defying Lipinski’s Accepted: 16 February 2021 Rule of 5 (Ro5) [3]; their molecular weight exceeds 500 Da and they have higher number of Published: 18 February 2021 hydrogen bond donor and acceptors than the traditional small molecules. As a result, they are more potent but their permeability, solubility, and metabolic clearance are negatively Publisher’s Note: MDPI stays neutral impacted. Nonetheless, it was speculated that the high potency and specificity might com- with regard to jurisdictional claims in pensate for the poor bioavailability and converge into reasonable oral doses [4]. The novel published maps and institutional affil- bifunctional small molecules called PROTACs (proteolysis-targeting chimeras) exploit iations. ubiquitin-proteasome system (UPS) machinery to degrade disease-causing intracellular proteins [5]. The first two orally bioavailable PROTACs, ARV-110, and ARV-471, target androgen receptor for prostate cancer and estrogen receptor for breast cancer, respectively, and are in clinic since 2019 [6,7]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 2008. https://doi.org/10.3390/ijms22042008 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 2008 2 of 39 Table 1. Approved small molecules by the Center for Drug Evaluation and Research (CDER) of the U.S. Food and Drug Administration (FDA) in oncology (2015–2020). Approval Dosage FDA Trade Name Drug Name Sponsor Properties Indication Year Form Review CDK4 and CDK6 Advanced (metastatic) breast Ibrance Palbociclib Pfizer Capsule P,B,A inhibitor cancer Progressive, differentiated thyroid cancer (DTC) whose disease progressed despite Lenvima Lenvatinib Eisai VEGFR inhibitor Capsule P,O receiving radioactive iodine therapy (radioactive iodine refractory disease). Histone deacetylase Farydak Panobinostat Novartis Multiple myeloma Capsule P,O,A inhibitor Locally advanced basal cell carcinoma that has recurred Smoothened following surgery or radiation Odomzo Sonidegib Novartis Capsule S inhibitor therapy, or who are not candidates for surgery or radiation therapy. Thymidine phosphorylase An advanced form of colorectal Trifluridine Lonsurf Taiho inhibitor plus a cancer who are no longer Tablet S and tipiracil nucleoside responding to other therapies 2015 metabolic inhibitor Specific soft tissue sarcomas (STS) – liposarcoma and Johnson & leiomyosarcoma – that cannot Yondelis Trabectedin Alkylating drug Injection P,O Johnson be removed by surgery (unresectable) or is advanced (metastatic). To be used in combination with vemurafenib to treat advanced melanoma that has spread to other parts of the body or can’t Cotellic Cobimetinib Genentech MEK inhibitor Tablet P,O be removed by surgery, and that has a certain type of abnormal gene (BRAF V600E or V600K mutation) Tagrisso Osimertinib AstraZeneca EGFR inhibitor Non-small cell lung cancer Tablet P,O,B,A Multiple myeloma who have Oral proteasome Ninlaro Ixazomib Takeda received at least one prior Capsule P,O inhibitor therapy Alecensa Alectinib Roche ALK inhibitor ALK-positive lung cancer Capsule P,O,B,A For chronic lymphocytic leukemia in patients with a Venclexta Venetoclax AbbVie BCL-2 inhibitor Tablet P,O,B,A specific chromosomal abnormality A new diagnostic imaging Fluciclovine Radioactive Axumin Blue Earth agent to detect recurrent Injection P 2016 F 18 diagnostic prostate cancer Advanced A diagnostic imaging agent to Gallium Ga Radioactive NETSPOT Accelerator detect rare neuroendocrine Injection P,O 68 dotatate diagnostic Applications tumors Clovis Rubraca Rucaparib PARP inhibitor A certain type of ovarian cancer Tablet P,O,B,A Oncology Postmenopausal women with a Kisqali Ribociclib Novartis CDK4/6 inhibitor Tablet P,B type of advanced breast cancer For the maintenance treatment 2017 for recurrent epithelial ovarian, Zejula Niraparib Tesaro PARP inhibitor Capsule P,O,B fallopian tube or primary peritoneal cancers Int. J. Mol. Sci. 2021, 22, 2008 3 of 39 Table 1. Cont. Approval Dosage FDA Trade Name Drug Name Sponsor Properties Indication Year Form Review Anaplastic lymphoma kinase Ariad Phar- (ALK)-positive metastatic Alunbrig Brigatinib maceuticals/ ALK inhibitor non-small cell lung cancer Tablet P,O,B,A Takeda (NSCLC) who have progressed on or are intolerant to crizotinib Acute myeloid leukemia, Rydapt Midostaurin Novartis FLT3 inhibitor advanced systemic Capsule P,O,B mastocytosis Puma EGFR, HER2 and Neratinib To reduce the risk of breast Nerlynx Biotechnol- HER4 irreversible Tablet S maleate cancer returning ogy kinase inhibitor Relapsed or refractory acute Idhifa Enasidenib Celgene/Agios IDH2 inhibitor Tablet P,O myeloid leukemia Aliqopa Copanlisib Bayer PI3Kα/δ inhibitor Relapsed follicular lymphoma Injection P,O,A Advanced or metastatic breast Verzenio Abemaciclib Eli Lilly CDK4/6 inhibitor Tablet P,B cancers AstraZeneca/Acerta Calquence Acalabrutinib BTK inhibitor Mantle cell lymphoma Capsule P,O,B,A Pharma Johnson & Androgen receptor Erleada Apalutamide Prostate cancer Tablet P Johnson inhibitor Array Unresectable or metastatic Braftovi Encorafenib BRAF inhibitor Capsule S,O BioPharma melanoma Array Unresectable or metastatic Mektovi Binimetinib MEK inhibitor Tablet S,O BioPharma melanoma Agios Phar- Relapsed or refractory acute Tibsovo Ivosidenib IDH1 inhibitor Tablet P,O maceuticals myeloid leukemia Relapsed or refractory chronic lymphocytic leukemia, small Copiktra Duvelisib Verastem PI3K inhibitor Capsule P,O,A lymphocytic lymphoma, and follicular lymphoma 2018 Metastatic non-small-cell lung Vizimpro Dacomitinib Pfizer EGFR inhibitor Tablet P,O cancer Talzenna Talazoparib Pfizer PARP inhibitor Metastatic breast cancer Capsule P Anaplastic lymphoma kinase ALK and ROS1 Lorbrena Lorlatinib Pfizer (ALK)-positive metastatic Tablet P,O,B,A inhibitor non-small cell lung cancer Acute myeloid leukemia or Hedgehog pathway Daurismo Glasdegib Pfizer high-risk myelodysplastic Tablet P,O inhibitor syndrome TRKA, TRKB and Loxo Oncol- Metastatic solid tumors with Vitrakvi Larotrectinib TRKC Capsule P,O,B,A ogy/Bayer NTRK-fusion proteins inhibitor Catalyst Potassium channel Xospata Gilteritinib Pharmaceuti- Acute myeloid leukemia Tablet P,O,B blocker cals Locally advanced or metastatic Balversa Erdafitinib Janssen/J&J FGFR inhibitor Tablet P,B,A bladder cancer Advanced or metastatic breast Piqray Alpelisib Novartis PI3K inhibitor Tablet P cancer Karyopharm Relapsed or refractory multiple 2019 Xpovio Selinexor XPO1 inhibitor Tablet P,O,A Therapeutics myeloma Androgen receptor Nubeqa Darolutamide Bayer Non-metastatic prostate cancer Tablet P inhibitor Daiichi CSF1R, KIT and FLT3 Symptomatic tenosynovial Turalio Pexidartinib Capsule P,O,B Sankyo inhibitor giant cell tumor Int. J. Mol. Sci. 2021, 22, 2008 4 of 39 Table 1. Cont. Approval Dosage FDA Trade Name Drug Name Sponsor Properties Indication Year Form Review Metastatic non-small cell lung TRKA, TRKB, TRKC, cancer and locally advanced or Rozlytrek Entrectinib Roche ROS1 and ALK Capsule P,O,B,A metastatic solid tumors with a inhibitor specific genetic defect Brukinsa Zanubrutinib BeiGene