Clinical Oncologist IQVIA, Hematology and Oncology IQVIA, Medical Strategy and Science, Therapeutic Science & Strategy Unit, Ing. Butty 275 9, C1001 CABA, ArgentinaArgentina
Complex Systems Lab, INFIP, FCEyN, Universidad de Buenos Aires - CONICET, Buenos Aires, ArgentinaArgentina
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Even though cancer researchers nowadays are trying to develop many key cellular pathways susceptible to be tackled by therapeutic approaches, we are far from being able to consider some cancers as curable diseases in general terms. From a pharmacodynamic point of view, the main potential molecular targets involved are driver oncogenes, tumor suppressor genes, growth factors and their receptors, transcription factors, tyrosine kinases, and cell adhesion molecules. If we consider possible targets at higher organization levels, we can intervene in aspects such as chromatin organization, tumor microenvironment, angiogenesis, apoptosis, senescence, mitochondria metabolism, and immune pathways.
Open Journal PUBLISHERS Opinion Cancer Dynamics 1* 2 Daniel Gandia, MD1*; Cecilia Suárez, PhD2 th 1Clinical Oncologist IQVIA, Hematology and Oncology IQVIA, Medical Strategy and Science,Therapeutic Science & Strategy Unit, Ing. Butty 275 9th, C1001 CABA, Argentina 2Complex Systems Lab, INFIP, FCEyN, Universidad de Buenos Aires - CONICET, Buenos Aires, Argentina * *Corresponding author Daniel Gandia, MD th Clinical Oncologist IQVIA, Hematology and Oncology IQVIA, Medical Strategy and Science,Therapeutic Science & Strategy Unit, Ing. Butty 275 9th, C1001 CABA, Argentina; Phone. 5411 4132 6516; E-mail: Daniel.Gandia@iqvia.com Article information rd rd th th Received: March 23 , 2020; Revised: April 23 , 2020; Accepted: April 30 , 2020; Published: May 14 , 2020 Cite this article Gandia D, Suarez C. Cancer dynamics. Cancer Stud Mol Med Open J. 2020; 6(1): 1-4. doi: 10.17140/CSMMOJ-6-130 ven though cancer researchers nowadays are trying to develop that is directed to the G12C niche within K-Ras, are being tested many key cellular pathways susceptible to be tackled by thera- nowadays in the clinics with promising results in some tumors E peutic approaches, we are far from being able to consider some such as advanced non-small-cell lung cancers. Other cellular-re- cancers as curable diseases in general terms. From a pharmaco- lated Ras pathways such as phosphatidylinositol-3-kinase (PI3K/ dynamic point of view, the main potential molecular targets in- AKT) and mammalian target of rapamycin (mTOR) have their volved are driver oncogenes, tumor suppressor genes, growth fac- own designed drugs that proved their worth, though to a lesser tors and their receptors, transcription factors, tyrosine kinases, and extent, in some tumor clinical settings.4 cell adhesion molecules. If we consider possible targets at higher organization levels, we can intervene in aspects such as chromatin Regarding tumor suppressor genes, things tend to be- organization, tumor microenvironment, angiogenesis, apoptosis, come more difficult and challenging for the moment, as a puta- senescence, mitochondria metabolism, and immune pathways. tive therapeutic agent must restore something that is missing or grossly inefficient. P53, one of the deoxyribonucleic acid (DNA) On the other hand, the Pan-cancer genome and tran- guardians and most well-known tumor suppressor genes, is be- scriptome have been analyzed in more than 1500 pediatric leuke- ing part of intensive research in relation to drugs that can “do mias and solid tumors. This analysis evidenced, for example, that something” at this level.5 Nevertheless, more than one hundred pediatric central nervous system tumors are genetically different different P53 mutations yet described tell us about its complexity. from their adult counterparts. In the meantime, whole-genome sequencing analysis of more than 2,500 tumors has already been Growth factor family and their related receptor path- done which is a continuing evolving genomic effort. A recon- ways are other branches of intensive research with clinical suc- struction of the life history and evolution of mutational process- cess. The discovery of the human epidermal growth factor re- es and driver mutation sequences of 38 types of tumors have ceptor (HER) family, a transmembrane epidermal-growth-factor been throughout analyzed in detail. This unveiled different chro- (EGF) family of receptors, has been one of the outstanding basic mosomal and gene abnormalities are present at different stages cancer research achievements of the past three decades with im- of the tumorigenesis process.1 mediate clinical translation impact: HER-2 has been found to be completely blocked by Herceptin (Trastuzumab), a monoclonal All the aforementioned means an essential part of the antibody, combined with chemotherapy, has saved many lives in fascinating cancer machinery and the new therapeutics that have HER-2 positive early and advanced breast cancer.6 been designed for many of the cellular targets are described with different levels of success. Regarding oncogenes, it´s noteworthy Other “cousins” of Herceptin are also already in the that the RAS family, one of the most important and frequently clinical setting, proving their efficacy and medical benefits: Per- mutated in many tumors, has not received a “knock-out” yet, tuzumab, Trastuzumab emtansine, Lapatinib, etc. Another clas- turning this family as the “Muhammad Ali” of this cancer story.2 sic EGF receptor family blocker, Cetuximab, has rendered good clinical results when combined with chemotherapy in wild-type Some recently developed novel drugs such as AMG 510, Kirsten rat sarcoma viral oncogene homolog (K-RAS) advanced cc Copyright 2020 by Gandia D.This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which 7,8 and recurrent colorectal and squamous head and neck cancers.7,8 One of the first “mammoths”, able to disrupt the devel- opment of these new capillaries by targeting the vascular endo- Tyrosine kinases (TKS) are other neuralgic druggable thelial growth factor receptor (VEGFR), was the monoclonal an- targets. Anticancer agents of novel molecular design types, the tibody Bevacizumab. With this drug, the treatment of advanced so-called “small molecules”, can act as inhibitors of the uni-ki- and non-advanced colorectal, cervical and ovarian cancers be- nase or multi-kinase TKS points and their downstream pathways came a reality. At present, continuous research in this area has de- (mTOR, AKT). The “first in class” of this kind of inhibitors was veloped fewer toxic antiangiogenics (“less bleeding ones”, mainly Imatinib, “the drug of the new millennium” (launched in 2001), of the small-molecules type) that are already in the clinical arena 10,14 specifically designed to target the TK domain within the Phila- (already mentioned “renal cancer drugs” are some examples). delphia chromosome BCR-ABL region in chronic myeloid leuke- mias. This drug is used to treat, with outstanding results (overall Cancer immunology today highlights its relevance as a survival of more than 15-years), refractory patients previously “new cancer science”. George Bernard Shaw was right, in “The considered as chemo-reluctant.9 doctor´s dilemma” play from 1906, when one of the actors states: “there is at bottom only one genuine scientific treatment for all diseases and A very recent review10 emphasizes that there are current- that is to stimulate phagocytes”. This was unconsciously referring to ly more than fifty small molecules that function as TKS inhibi- the innate immunology. The same type of discovery was made tors used to treat a broad spectrum of malignancies. Renal clear by Metchnikoff, “the father of phagocytosis”, nearly at the same cell carcinoma is a type of tumor that has obtained an important time.15 clinical benefit from these kinds of compounds (Sunitinib, Pazo- panib, Sorafenib). Considering other druggable targets, transcrip- There are different types of these kinds of immune tion factors are at present a current area of new and intensive therapies, but at present, the most explored and promising ones research, with many transcription factor inhibitors in early clinical are the checkpoint inhibitors (CPIs).16 Monoclonal antibodies phases of development.11 such as Ipilimumab, Nivolumab, and Pembrolizumab are com- pounds of this class, leading to a new therapeutic concept in can- Chromatin organization/reorganization in cancer is cer immunology. These compounds allow natural killer cells “to complex, and its implications in euchromatin/heterochroma- eat tumors”, strictly speaking, inhibiting or eliminating the nega- tin rate, “readable” genes, nucleosome composition and cell epi- tive immune regulation induced by the tumor.17 genetics, are other future challenging roads to go through. This led to the appearance of epigenetic therapy. Hypomethylating CPIs demonstrated a significant increment in advanced agents are chromatin-targeted drugs with known beneficial ef- melanoma survival, with important visceral responses and achiev- fects in hematologic premalignancy as myelodysplastic syndromes ing, in some cases, complete responses, “the cure”. This made to and some blood cancers such as acute myeloid leukemia (AML).12 recall the prior days as a Resident in Oncology. At that time, in 1987, Dr. Steven Rosenberg’s discovery was fascinating such as But cancer also develops many more alterations at high-dose interleukin-2 treatment delivered in the Intensive Care higher organization levels than the molecular one. At the cellular Unit that rendered some patients with peculiar tumor responses, level, this means self-suffiency to growth signals, evasion from mainly in renal cancers and melanoma.18 And when complete, growth-inhibitory ones, evasion from apoptosis, limitless replica- they were long-lasting! This was, by that time, the best immuno- tive potential, survival after cell-cell detachment, altered energy therapy ever known. Unfortunately, it was toxic. The cytokine and metabolism, and acquisition of other special capabilities. Among white blood cell storm induced by these high doses of interleu- these last ones, cell motility, invasiveness, and survival during the kin-2 was in some cases the cause of the patient’s death. Hence, travel and settlement in new and not-friendly metastatic niches.13 this treatment was avoided.
Tumor cells may also acquire not only immunologic escape abili- ties but also the power of inducing T-cell death. At the tissue Nowadays, CPIs such as Pembrolizumab are standard level, there are marked alterations in fluid dynamics, as normal of care in different tumor settings as head and neck cancer, re- plasma passage to tissues is subjected to more interstitial pressure nal cell carcinoma, non-small cell lung cancer, liver cancer, and constraints and a new set of capillaries developed through neo- microsatellite instability- (MSI) agnostic tumors. More “complex- angiogenesis.
designed” immunotherapies are both in early and advanced devel- opmental phases, such as novel vaccines and oncolytic therapies For all these pharmacodynamic roads to target, only with adenoviruses. Finally, chimeric antigen receptor (CAR) T-cell the angiogenesis inhibition and immune-directed therapies have therapy is a newly designed concept that has changed the natural proved to be important therapeutic tools today in the clinical are- history of some advanced refractory blood cancers, yet to prove na. Angiogenesis is key in tumor feeding and an inflection point its worth with solid tumors.19 to tumor malignization. Nutrients and oxygen are delivered to the cancer cells from new modified “tube formation”: an abnormal Regarding higher organization levels like tumor tis- and fenestrated capillary network that results in heterogeneous sue structure and pathophysiology, other complex factors of and rather chaotic tumor irrigation that difficult the administra- tumorigenesis came up to focus, such as cell de-differentiation, tion of therapeutic agents.
epithelial-mesenchymal transitions, tumor mutation rate, clonal expansion rates, and complex and dynamic cellular interactions. tol-3-kinase growth disorders and cancer. N Engl J Med. 2018; Among these, different competitions and cooperations take place 379(21): 2052-2062. doi: 10.1056/NEJMra1704560 between tumor clones, tumor cells from different differentiation stages (for example, proliferating tumor cell/tumor stem cell rate) 5. Muller P, Vousden K. Mutant p53 in cancer: New functions and between tumor cells and other cells from the microenviron- and therapeutic opportunities. Cancer Cell. 2014; 25: 304-317. doi: 20,21 ment.
10.1016/j.ccr.2014.01.021 Indeed, the whole tumor microenvironment may be 6. Hayes DF. HER2 and breast cancer: A phenomenal success completely altered, as previously normal cells from the stroma story. N Engl J Med. 2019; 381(13): 1284-1286. doi: 10.1056/ (fibroblasts, adipocytes) may have been converted by the tumor NEJMcibr1909386 in tumor-associated cells that begin to work for its maintenance.22 All these mentioned cellular processes lead to a different level of 7. Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. tumor complexity and heterogeneity, becoming this last one, the Colorectal cancer. The Lancet. 2019; 394: 1467-1480. doi: 10.1016/ main cause of treatment resistance, and tumor recurrence. This S0140-6736(19)32319-0 converts all these phenomena into a fascinating and challenging druggable target.
8. Chow LQM. Head and neck cancer. N Engl J Med. 2020; 382(1): 60-72. doi: 10.1056/NEJMra1715715 From an integrative point of view, cancer involves dy- namic genetic alterations as well as tumor-host interactions that 9. Claudiani S, Apperley J. The argument for using imatinib in determine the destiny of the tumor and the host.23 Among the CML. Hematology Am Soc Hematol Educ Program. 2018; 2018(1): last ones, and settled at the whole-organism organization level, 161-167. doi: 10.1182/asheducation-2018.1.161 tumorigenesis begins with a great demand for nutrients from the tumor that cannot be satisfied by the host. This causes tumor cells 10. Bedard P, Hyman D, Davids M, Siu L. Small molecules, big to reside in a dismal environment that induces glycolytic meta- impact: 20 years of targeted therapy in oncology. Lancet. 2020; bolic shifts; angiogenesis; and force cells to invade, metastasize, 395: 1078-1088. doi: 10.1016/S0140-6736(20)30164-1 and undergo necrosis. Tumor necrosis, particularly in metastases, leads to non-specific systemic inflammation, which is the major 11. Stathis A, Bertoni F. BET proteins as targets for anticancer cause of cancer-related mortality.
treatment. Cancer Discov. 2018; 8(1): 24-36. doi: 10.1158/2159- 8290.CD-17-0605 In the end, in front of a cancer patient and considering all the aforementioned scenarios with a critical eye, we can sum- 12. Mei M, Aldoss I, Marcucci G, Pullarkat V. Hypomethylating marize them in four ones. First, which are the tumor oncogenic agents in combination with Venetoclax for acute myeloid leuke- drivers and which the more irrelevant mutations. Second, which mia: Update on clinical trial data and practical considerations for are the main underlying mechanism/s of tumor progression. use. Am J Hematol. 2019; 94(3): 358-362. doi: 10.1002/ajh.25369 Third, how is the inner cell dynamics of the tumor? And fourth, how is the tumor-host interaction. All these four scenarios can 13. Hanahan D, Weinberg R. Hallmarks of cancer: The next gen- help us, not only for making better use of old and novel thera- eration. Cell. 2011; 144: 646-674. doi: 10.1016/j.cell.2011.02.013 peutic agents in use but also with the more complex coming ones that will specifically target cellular dynamics.
14. Qiao Y, Dsouza C, Matthews AA, Jin Y, He W, Bao J, et al. Discovery of small molecules targeting GRP78 for antiangiogen- CONFLICTS OF INTEREST ic and anticancer therapy. Eur J Med Chem. 2020; 193: 112228. doi: 10.1016/j.ejmech.2020.112228 The authors declare that they have no conflicts of interest. 15. Teti G, Biondo C, Beninati C. The phagocyte, Metchnikoff,