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Theranostics 2019; 9(18):5149-5165. doi:10.7150/thno.31657 This issue Cite

Research Paper

Decoding cancer heterogeneity: studying patient-specific signaling signatures towards personalized cancer therapy

Efrat Flashner-Abramson^1#, Swetha Vasudevan^1#, Ibukun Adesoji Adejumobi¹, Amir Sonnenblick², Nataly Kravchenko-Balasha^1,✉

1. Department for Bio-medical Research, Institute of Dental Sciences, Hebrew University of Jerusalem, Jerusalem 91120, Israel
2. Oncology Division, Tel Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
^# Equal contribution

✉ Corresponding author: natalykhuji.ac.il

Abstract

The past years have witnessed a rapid increase in the amount of large-scale tumor datasets. The challenge has now become to find a way to obtain useful information from these masses of data that will allow to determine which combination of FDA-approved drugs is best suited to treat the specific tumor. Various statistical analyses are being developed to extract significant signals from cancer datasets. However, tumors are still being assigned to pre-defined categories (breast luminal A, triple negative, etc.), conceptually contradicting the vast heterogeneity that is known to exist among tumors, and likely overlooking unique tumors that must be addressed and treated individually. We present herein an approach based on information theory that, rather than searches for what makes a tumor similar to other tumors, addresses tumors individually and unbiasedly, and impartially decodes the critical patient-specific molecular network reorganization in every tumor.

Methods: Using a large dataset obtained from ~3500 tumors of 11 types we decipher the altered protein network structure in each tumor, namely the patient-specific signaling signature. Each signature can harbor several altered protein subnetworks. We suggest that simultaneous targeting of central proteins from every altered subnetwork is essential to efficiently disturb the altered signaling in each tumor. We experimentally validate our ability to dissect sample-specific signaling signatures and to rationally design personalized drug combinations.

Results: We unraveled a surprisingly simple order that underlies the extreme apparent complexity of tumor tissues, demonstrating that only 17 altered protein subnetworks characterize ~3500 tumors of 11 types. Each tumor was described by a specific subset of 1-4 subnetworks out of 17, i.e. a tumor-specific altered signaling signature. We show that the majority of tumor-specific signaling signatures are extremely rare, and are shared by only 5 tumors or less, supporting a personalized, comprehensive study of tumors in order to design the optimal combination therapy for every patient. We validate the results by confirming that the processes identified in the 11 original cancer types characterize patients harboring a different cancer type as well. We show experimentally, using different cancer cell lines, that the individualized combination therapies predicted by us achieved higher rates of killing than the clinically prescribed treatments.

Conclusions: We present a new strategy to deal with the inter-tumor heterogeneity and to break down the high complexity of cancer systems into simple, easy to crack, patient-specific signaling signatures that guide the rational design of personalized drug therapies.

Keywords: Personalized medicine, cancer combination therapy, information theory, protein networks, cell signaling, patient-specific network reorganization

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