Hematology and Oncology, Medical Strategy & Science,Therapeutic Science & Strategy Unit, Ing. Butty 275 9 , C1001 CABA, ArgentinaArgentina
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Some tumor types such as testicular cancer, leukemia and lymphomas, have their origin in cells that comport a common embryonic origin. This phenomenon was “unconsciously” the roadmap to treat and cure them by classic chemotherapy. The cells are very chemosensitive indeed as they are “immature” in origin.
Open Journal PUBLISHERS Opinion The Phenotype Landscape of Cancer in the Genotype Era * Daniel Gandia, MD* th Hematology and Oncology, Medical Strategy & Science,Therapeutic Science & Strategy Unit, Ing. Butty 275 9th, C1001 CABA, Argentina * *Corresponding author Daniel Gandia, MD th Clinical Oncologist, Hematology and Oncology, Medical Strategy & Science,Therapeutic Science & Strategy Unit, Ing. Butty 275 9th, C1001 CABA, Argentina; Office. 5411 4132 6516; Mobile. 54911 6496 5444; E-mail: Daniel.Gandia@iqvia.com Article information th th nd th Received: September 15 , 2019; Revised: October 17 , 2019; Accepted: October 22 , 2019; Published: October 24 , 2019 Cite this article Gandia D. The phenotype landscape of cancer in the genotype era. Cancer Stud Mol Med Open J. 2019; 5(1): 26-27. doi: 10.17140/CSMMOJ-5-129 ome tumor types such as testicular cancer, leukemia and lym- But, all the before-mentioned is a “partial win” in the phomas, have their origin in cells that comport a common em- treatment of cancers. There will be still continued exploring “for S bryonic origin. This phenomenon was “unconsciously” the road- more and better” in the above-targeted therapy.
map to treat and cure them by classic chemotherapy. The cells are very chemosensitive indeed as they are “immature” in origin. The answer for therapy failures is related to the old con- cept of tumor heterogeneity. Imagine a view with the light micro- Chemotherapy has also positively impacted the overall scope, where the tumor sample even seeming homogeneous, is survival of some pediatric and adolescent cancers (leukemias, composed of “cells of different imaginable colors”. Tumor cell lymphomas, bone tumors) and in many other adult ones such phenotype heterogeneity is the main cause of secondary resis- as breast, ovarian, head and neck and colorectal cancers. Despite tance and also of progression in the already mentioned chemo- everything, we also face other difficult to treat cancers which re- sensitive tumors, and one of the main causes of the non-tumor main chemo resistant (lung, melanomas, pancreatic, biliary tract responses in the less de novo chemosensitive ones such as lung cancers as the most representative ones).
As basic and translational cancer researches evolve, Nowadays, tumor heterogeneity explains why therapy these tumor-types have turned into a significant focal point of targeted to a driver gene or protein in a tumor is met with disease intrigue. So, what to do in order to work-out this cancer resis- progression, the disease at some point now it has a new driver tance dilemma? Targeting some tumor genetic mutations such gene in some cells, or more easily the emerging presence of a new as those of the tyrosine kinase types, oncogene- driven growth clonal cell population. So, is the answer we need to explore for factor receptors and some immune molecules such as those of new biomarkers? Yes or no.
the programmed-death pathway (PD-1 and PD-L1) and the cyto- toxic T-lymphocyte-associated protein 4 (CTLA4) axis, enable us Tumor heterogeneity is something more than this, it´s to battle the malignant growth.
mainly the cellular dynamics between the different tumor clones that lead to resistance. These dynamics are essential to the pheno- Regarding these aforementioned cellular pathways, typic landscape of the cancer cell populations. Tumor cells have drugs which are of small molecules, target the first two drug- a “great talk” between them (growth factors signals). They have gable ones and treat lung, renal and malignant melanoma. The cooperation within the different clones: two clones evolve com- third one, “the mammoths”: monoclonal antibodies (MABs), can plementary traits. Even though each clone is not self-sufficient, disrupt angiogenic pathways, block some oncogenic drivers (such their cooperation results in malignancy.
as RAS) and mainly deblock the lazy T-lymphocytes by allowing them to “eat tumors” (checkpoint inhibitors to treat melanoma, They have competition for oxygen and substrates, and lung, squamous head and neck tumors). This last one, became the also interactions with the mesenchyme in the case of epithelial tu- treatment of cancer by the inhibition of negative immune regula- mors. In this sense, clonal lineages with similar fitness may coex- tion for which the researchers have been granted Nobel prize.1 ist and compete within a tumor, a phenomenon known as clonal interference. This adds a higher complexity to the cancer-disease cc Copyright 2019 by Gandia D. This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which allows to copy, redistribute, remix, transform, and reproduce in any medium or format, even commercially, provided the original work is properly cited. Cancer Stud Mol Med Open J. 2019; 5(1): 26-27. doi: 10.17140/CSMMOJ-5-129 process. In origin, cancer is a one-cell-disease but, it is a tissue eradicating the tumor. Similarly, an immune-desert phenotype disrupted-related disease during the rest of its whole lifecycle. can be the result of immunological ignorance, the induction of With the old, current and novel drug-tools, we must learn “how tolerance or a lack of appropriate T-cell priming or activation. to treat the cancer phenotype in a better way.” In the early days of Immune-excluded tumors may reflect a specific chemokine state, chemo, in some way all the aforementioned have been taken into the presence of particular vascular factors or barriers, or specif- account: tumor cellular kinetics explained by the Goldie-Coldman ic stromal-based inhibition. Finally, inflamed tumors can dem- model measures genetic instability to the probability of a tumor onstrate infiltration by a number of subtypes of immune cells containing drug-resistant clones. This works as a framework for (T-cells, myeloid-derived suppressor cells, suppressor B-cells and understanding some types of tumor cell kinetics and posterior cancer-associated fibroblasts such as in Melanoma). chemo responses and resistance in them.
Finally, for some difficult to treat cancer scenarios, My opinion here is to highlight the tumor heterogeneity where the disease has a progression over progressions or are with its clonal dynamics as a whole: the Cancer Phenotype. directly refractories ones, the medical therapy to be utilized are in an adaptive or metronomic manner, directed to some tumor Cancer can also be considered as an evolutive Darwinian cell populations while keeping up calm on others with the lesser process, where the most adaptable cancer cells within a hetero- growth (e.g., mesothelioma, pancreatic carcinomas, biliary tract geneous population survives, proliferate and invade other organ- cancers mainly).
sites. Phenotype plasticity is an enabler of tumor progression and therapy resistance. Within it, is tumor heterogeneity what makes Some cancers can be considered as chronic diseases. As malignancies as the “masters of evasion”.
a physician, the “primum non-nocere” concept is essential: “to treat the patient, not just the cancer”.
On the other hand the tumor immunophysiology, the scenario is even more complex in its phenotypic assessment, with