Progress in the Development of Preventative Drugs for Cisplatin

Jan 23, 2018 - In 2016, he received his PhD in organic chemistry from Purdue University, where he worked in the laboratory of David A. Colby on synthe...
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Progress in the Development of Preventative Drugs for Cisplatin-Induced Hearing Loss Robert Alan Hazlitt, Jaeki Min, and Jian Zuo J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.7b01653 • Publication Date (Web): 23 Jan 2018 Downloaded from http://pubs.acs.org on January 23, 2018

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Journal of Medicinal Chemistry

Progress in the Development of Preventative Drugs for Cisplatin-Induced Hearing Loss Robert A. Hazlitt,†,‡ Jaeki Min,‡ Jian Zuo*,† †

Dept. of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN

38105, USA ‡

Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital,

Memphis, TN 38105, USA

ABSTRACT: Cisplatin is a highly effective treatment for malignant cancers and has become a cornerstone in chemotherapeutic regimens. Unfortunately, its use in the clinic is often coupled with a high incidence of severe hearing loss. Over the past few decades, enormous effort has been put forth to find protective agents that selectively protect against the ototoxic side effects of cisplatin and not interfere with its antitumoral activity. Many therapies have been successful in preclinical work, but only a few have shown any protection in the clinic, and none have been approved by the FDA. This review summarizes the clinical and preclinical studies of the most effective small molecule candidates currently in clinical trials, while also detailing their molecular mechanisms of action, to gain insight for future drug development in the field.

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Since its approval by the FDA in 1978, cisplatin has become a cornerstone in chemotherapeutic regimens and has been included on the World Health Organization’s list of essential medicines. However, its therapeutic benefits are often coupled with potentially debilitating ototoxicity, with some degree of hearing loss occurring in about 63% of patients.1 Despite the high incidence and the enormous social and economic consequences of the ototoxic side effects, no FDA approved therapies for prevention of cisplatin-induced hearing loss have been developed. Still, numerous protective compounds have been identified in preclinical studies and several are currently undergoing clinical trials (Table 1 and Figure 1). Table 1. List of all clinical candidates for protection against cisplatin-induced ototoxicity

Name

Mechanism

Delivery

Outcomes and Considerations

Completed

Ref.

I.V.

2017

Sodium thiosulfate

Lowered incidence of hearing loss; Lowered survival for disseminated cancer

2

inactivates cisplatin; antioxidant; protects antioxidant enzymes

I.V.

No results reported

ETC 2018

3

I.A.

No impact on incidence of hearing loss

2007

4

Acetylcysteine

D-methionine

Amifostine

inactivates cisplatin; antioxidant; protects antioxidant enzymes; promotes glutathione synthesis

I.V.

Dose finding study; no results reported

ETC 2019

5

Local

Significant hearing protection only at 8 kHz

2013

6

Local

No significant hearing protection

2014

7

inactivates cisplatin; antioxidant; protects antioxidant enzymes

Oral

Reported hearing protection at >10 kHz; No peer-reviewed data published

2009

8

I.V.

Non-randomized; hearing protection in average-risk, but not high-risk medulloblastoma

2014

9

I.V.

Ototoxicity in amifostine group (9%) vs untreated (16%)

1996

10

I.V.

(5 Trials) No significant hearing protection

1999-2009

11-15

Oral

Ongoing study; No results reported

ETC 2018

16

Local

Negative efficacy results in a related study

Terminated

17

Local

Significant hearing protection only at 6 kHz

2013

18

inactivates cisplatin; antioxidant

Ebselen

antioxidant; glutathione peroxidase mimetic; anti-inflammatory

Dexamethasone

regulates cytokines; protects antioxidant enzymes

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Journal of Medicinal Chemistry

Flunarizine

inhibits MPT and NF-κB activation

Oral

Significant hearing protection at