Metastasis is the deadliest feature of cancer, accounting for greater than 90% of cancer-related mortality. The clinical manifestation of metastatic lesions is the end result of a treacherous journey that few tumor cells are capable of completing, including local invasion and intravasation, survival in the circulation, homing and extravasation into the parenchyma of distant organs, and finally, adaptation to the new environment and outgrowth of secondary lesions. Development of successful therapeutic strategies to specifically target metastasis depends on understanding tumor-intrinsic and extrinsic mechanisms that dictate metastatic behaviors, the metastatic niches for the seeding and outgrowth of metastases in different organ sites and the molecular features that render metastatic cancer resistant to current therapies.
The Ludwig Princeton Branch plays a leading role in the study of cancer metastasis, including signaling networks that regulate cellular plasticity during metastasis, stromal niches that regulate organ-tropic metastasis, metabolic adaptation of metastatic cancer cells, as well as the development of novel anti-metastasis therapeutic agents.
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Cararo-Lopes E, Sawant A, Moore D, Ke H, Shi F, Laddha S, Chen Y, Sharma A, Naumann J, Guo JY, Gomez M, Ibrahim M, Smith TL, Riedlinger GM, Lattime EC, Trooskin S, Ganesan S, Su X, Pasqualini R, Arap W, De S, Chan CS, White E. medRxiv. 2023 Mar 10:2023.03.09.23287037. doi: 10.1101/2023.03.09.23287037. Preprint. PMID: 36945575
Differentiated thyroid cancer (DTC) affects thousands of lives worldwide each year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) quality of life and might be unnecessary in indolent DTC cases. On the other hand, the lack of biomarkers indicating a potential metastatic thyroid cancer imposes an additional challenge to managing and treating patients with this disease.
Hailing Chen, Meimiao Zhan, Jianbo Liu, Zhihong Liu, Minhong Shen, Fenfang Yang, Yibin Kang, Feng Yin, Zigang Li. J Med Chem. 2022 Sep 22;65(18):12188-12199. Doi: 10.1021/acs.jmedchem.2c00862. Epub 2022 Aug 31. PMID: 36044768
Blocking the interaction of MTDH/SND1 complex is an attractive strategy for cancer therapeutics. In this work, we designed and obtained a novel class of potent stabilized peptide inhibitors derived from MTDH sequence to disrupt MTDH/SND1 interaction. Through structure-based optimization and biological evaluation, stabilized peptides were obtained with tight binding affinity, improved cell penetration, and antitumor effects in the triple-negative breast cancer (TNBC) cells without nonspecific toxicity. To date, our study was the first report to demonstrate that stabilized peptides truncated from MTDH could serve as promising candidates to disrupt the MTDH/SND1 interaction for potential breast cancer treatment.
Minhong Shen, Yibin Kang. Trends Cancer. 2022 Sep 29:S2405-8033(22)00190-X. doi: 10.1016/j.trecan.2022.08.007. Online ahead of print.PMID: 36184492
Development of cancer therapeutics has traditionally focused on targeting driver oncogenes. Such an approach is limited by toxicity to normal tissues and treatment resistance. A class of 'cancer fitness genes' with crucial roles in metastasis have been identified. Elevated or altered activities of these genes do not directly cause cancer; instead, they relieve the stresses that tumor cells encounter and help them adapt to a changing microenvironment, thus facilitating tumor progression and metastasis. Importantly, as normal cells do not experience high levels of stress under physiological conditions, targeting cancer fitness genes is less likely to cause toxicity to noncancerous tissues. Here, we summarize the key features and function of cancer fitness genes and discuss their therapeutic potential.