<p>Spotlight on aldoxorubicin (INNO-206) and its potential in the treatment of soft tissue sarcomas: evidence to date</p>

Abstract

Anthracyclines, and doxorubicin in particular, remain a mainstay of sarcoma therapy. Despite modest activity and significant toxicities, no cytotoxic monotherapy has yet yielded superior overall survival over doxorubicin for therapy of advanced soft tissue sarcomas in a randomized trial. Similarly, combination regimens have also been unable to overcome doxorubicin in terms of overall survival. Strategies to ameliorate the most prominent side effect of doxorubicin, cardiotoxicity, are available, but their use in sarcoma patients has been limited. Aldoxorubicin is a prodrug consisting of doxorubicin with a covalent linker. It binds rapidly after intravenous infusion to cysteine-34 of human serum albumin. The drug–albumin conjugate is preferentially retained in tumor tissue, with uptake into tumoral cells. At physiologic pH, the complex is stable. Hydrolysis can occur under the acidic conditions of the endocytic lysosome, releasing doxorubicin. Doxorubicin then distributes to various cellular compartments, including Golgi, mitochondrion, and nucleus, with subsequent cytotoxic effects. Aldoxorubicin has demonstrated in vitro and in vivo activities in both cancer model systems and human xenografts. Preclinical models also support its decreased cardiac effects vs doxorubicin, although such promising results require formal comparison at efficacy equivalent doses of the two drugs. Phase I studies confirmed the tolerability of aldoxorubicin in humans. Clinical cardiotoxicity was not observed, but molecular and subclinical cardiac effects could be demonstrated. A Phase II study in treatment-naïve, advanced sarcoma patients demonstrated improved progression-free survival and response rate over doxorubicin, although no survival benefit was evident. A Phase III study of aldoxorubicin vs investigator’s choice from a panel of chemotherapy regimens in the salvage setting was unable to demonstrate a benefit in progression-free or overall survival in the entire population. Progression-free survival in L-sarcomas (leiomyosarcomas and liposarcomas) was documented. While evidence of subclinical cardiac effects was seen in a small proportion of aldoxorubicin-treated patients, data from both the Phase II and III studies indicated a favorable cardiotoxicity profile vs doxorubicin. Despite the negative results from this Phase III study, the importance of anthracycline therapy in sarcoma management merits further investigation of the potential role of aldoxorubicin in this indication. Other avenues for progress include identification of sensitive histologies and biomarkers of activity, exploration of clinical niches without proven standard therapies, and exploration of alternate dosing strategies.

Shortwave Infrared-Emitting Theranostics for Breast Cancer Therapy Response Monitoring

“…Recently, atezolizumab with nab-Paclitaxel was approved as a combinatorial therapeutic for metastatic TNBC for a subpopulation of programed cell death ligand 1 (PD-L1)-positive patients with advanced metastatic breast cancer ( Heimes and Schmidt, 2019 ; Narayan et al, 2020 ; Reddy et al, 2020 ). However, chemotherapeutic agents are often associated with a relatively low response rate ( Lebert et al, 2018 ) and adverse side effects, such as cardiotoxicity in the case of Dox ( Zhao et al, 2018 ; Cranmer, 2019 ; Zhang et al, 2020 ). There is a critical need for monitoring TNBC therapy response in real time to provide altered regimen options early.…”

“…Nanoparticle delivery systems, such as liposomal, protein-based (e.g., albumin), and polymeric, have been shown to reduce systemic toxicity compared to free drug, as well as improved target site delivery, leading to increased drug concentration at the tumor site ( Senapati et al, 2018 ; Anselmo and Mitragotri, 2019 ). Albumin, in particular, as either a drug conjugate ( Cranmer, 2019 ) or nanocarrier ( An and Zhang, 2017 ), can improve circulation time of the drug ( Karami et al, 2020 ), facilitate increased tumor tissue accumulation via the enhanced permeability and retention (EPR) effect ( Kimura et al, 2018 ), and overcome drug resistance ( Onafuye et al, 2019 ). Adapting an effective delivery tool to address the lack of TDM has fueled recent research into a new field of theranostics.…”

Antitumour Anthracyclines: Progress and Perspectives

“…In turn, the acid‐labile hydrazone bond permits the release of doxorubicin under acidic conditions, such as in a tumour tissue environment and inside endosomes or lysosomes within tumour cells . Derivative 31 was also named DOXO‐EMCH„ INNO‐206 or aldoxorubicin …”

“…A phase II clinical trial with advanced soft tissue sarcoma patients, where 31 was administered every three weeks with 350 mg/m 2 , showed improvement in progression‐free survival of 5.6 months, compared to 2.7 months observed with doxorubicin regimen; but no significant overall survival was demonstrated. Unfortunately, the following phase III trial failed to demonstrate improvement even in the progression‐free survival endpoint …”

Targeting Toxins toward Tumors

“…The resulting albumin-linked drug ( 5 ) cannot penetrate into cells until the hydrazone is hydrolyzed in the acidic environment around cancer cells to provide the free doxorubicin ( 6 ; Scheme 2 ). The clinical phase III trial, however, did not enable registration of the compound as a drug [ 14 , 21 , 22 ]. Despite these preliminary results, attempts to overcome the cardiotoxicity of DOX-EMCH continue.…”