1- Nitrogen mustard in 1940’s is the result of a serendipitous discovery during the Second World War

This gave birth to this alkylating agent and its use in pediatric lymphoma [8]. Its use generated a lot of excitement which was soon followed by frustration due to tumor regrowth.

2- Fluorinated pyrimidines in 1950’s

Scientific experiments on hepatoma cell lines by Heidelberger gave birth to 5-FU, which is in use some 80 years later [9].

3- Platinum compounds in 1970’s

Another serendipitous discovery, this time by Einhorn, brought Cis-platinum into the treatment protocols of testicular cancer, leading to a breakthrough in its treatment and outcome [10].

4- Tamoxifen and Taxol of 1970s-1990s

Above agents represent the birth of targeted therapeutic and naturally occurring Compounds [11]. NCI of USA had around thirty thousand naturally occurring compounds on its shelf. Taxol and a lot of other naturally occurring compounds were among them.

Meanwhile, growth, proliferation and transduction pathways started to become targets of the next generation of cancer therapeutics. From this point on, explosion of knowledge in cancer biology and deeper understanding of living cell at DNA, RNA, Micro-RNA, Epigenome, Telomere, Gene regulatory pathways [12], Tumor Suppressor genes, Oncogenes, and Tumor Immunology [13] took the driver’s seat and led to yet another generation of cancer Therapeutic agents. Findings on microenvironment and tumor vasculature, and their interplay with tumor mass led to major breakthroughs such as development of Imids and Inhibitors of tumor vasculature such as Avastin [14].

In the last eighty years, cancer has been defined in many different ways, ranging from disorderly proliferation of dedifferentiated cells to disease of genome. Numerous changes in cancer definition and treatment in different eras has followed evolution in understanding the process of carcinogenesis [15].

Of interest, in the last eighty years we have continued to evolve into more sophisticated cancer cell killers [16]. This implies that we have continued to believe that we should kill cancer cells to cure our patients [17]. However, exceptions such as Imids [18] and differentiating agents such as Retinoids [19] that interfere with microenvironmental growth and survival signals as well as intracellular transduction pathways exist [20].

Regardless, for the most part we are dealing with insurmountable barriers. It is clear that we need to come up with true definition of cancer [21], in order to develop a solid foundation for development of next generation of cancer therapeutics [22]. This necessitates deep understanding of the interplay of the most fundamental law [23] that governs the homeostasis of living cell, namely the second law of thermodynamics [24], with cell function at all levels, including its birth, proliferation, and demise. The main reason for failure and limited success of numerous generations of cancer therapeutics so far, is that they have been built on a false or partial understanding of neoplastic transformation [25]. To avoid a similar destiny, we need to take one big step back and examine the real mechanism of initiation of mitosis [26] during different eras of life cycle of an organism, dating back to first mitosis following fertilization [27].

As far as the governing universal laws are concerned, two major events incessantly ensue fertilization, 1- crowding through addition of another 23 chromosomes to the closed space of ovum, 2- addition of totally unfamiliar paternal genetic imprinting to that of the maternal genetic imprinting of ovum (Figure 1).

Both of these two events significantly increase the cellular network entropy in no time [28]. As such, the second law of thermodynamics which is flowing in the matrix of living cell, gets disturbed in the sense that the foundation of living cell which is based on keeping the cellular network entropy at the lowest, is shaken. This disturbance, in a puzzling way leads to initiation of mitosis. This is akin to eruption of a volcano. The only goal of recurrent rounds of mitosis following fertilization [29] is minimizing the cellular network entropy, by materialization of paternal genomic imprinting more and more with each round of mitosis [30], and generating a new normal state by populating numerous cells and organ formation with the same number of chromosomes during embryogenesis. Available studies have shown further materialization of paternal genomic imprinting following each round of mitosis [31]. Destruction of paternal mitochondrion immediately following fertilization and loss of Y chromosome in males as they age lend further support to this concept [32]. A lot of disorders that we get afflicted with are the result of breakdown [33] of above-mentioned path (Figure 2).

To protect the integrity of the living cell and to keep the cellular network entropy at the minimum possible level as per the limit of the second law, evolution of living organisms has developed sensors [34] and executors [35] at each and every subcellular compartment of the cell. According to Murphy’s law [36], what could go wrong would go wrong. A diverse group of disease states are the result of dysfunction of sensors and executors [37]. In this regard, cancer is the prototype example. The net result is a significant increase in cellular network entropy in a very short period of time. Available mathematical models could measure master regulator network entropy of cell which represents above premises [38].

In contradistinction to cancer, cellular network entropy of an aged cell gets elevated over a matter of several decades [39]. That is why the vast majority of cancers are diagnosed in older people [40]. Consequently, true definition of cancer is neither uncontrolled proliferation of dedifferentiated cells, nor is it the disease of the genome [41]. Rather they are different manifestations of the breakdown of the fine interplay of the second law of thermodynamics with the living cell, which leads to massive increase in cellular network entropy in a very short period of time. This massive increase in entropy affects all the sub-compartments of the cell ranging from quaternary structure of cellular proteins [42] to micro-RNA network and epigenome [43]. One major reason, why despite the fact that in midlife cells of different organs are loaded with ill mutations, cancer is not prevalent [44], is the fact that cellular network entropy has not reached a critical level as yet.

Single cell sequencing technology [45], and existing mathematical models for calculation of master regulator complex network entropy, could enable us to derive spatial entropyomics [46] signature of evolutionary road map of tumor mass. As the forward evolutionary path of tumor mass along the thermodynamics arrow of time happens in quanta, each step in this forward move is guided by a new driver.

Consequently, there are numerous drivers along this path [47], in contradistinction to the current thinking of one driver, one cancer. The driver front is expected to have the highest master regulator complex network entropy. By using artificial Intelligence [48], one could predict the future of tumor mass, and take pre-emptive steps to slow down or block the forward evolutionary tumor road map.

Nanotechnology [49], and available nanodelivery methodologies, could enable us to modify the current and future driver front master regulator complex network entropy, and bring them close to the values of previous generation of drivers. As such, the forward move of tumor mass would cease or significantly slow down.

At times our nanomachines have to deliver a missing micro-RNA to the driver front [50], and on some occasions they would change the transmembrane electrostatic force [51].

These decisions need to be made by a team of scientists comprised by single cell sequencers [52], evolutionary biologists, mathematical biologists, and artificial intelligence specialists, in a customized fashion (Figure 3).

We have gone a long way since the introduction of nitrogen mustard as the first cancer treatment regimen in 1942. Multiagent chemotherapy protocols, hormonal therapy, targeted therapy, monoclonal antibodies, tumor vaccines, differentiating agents, microenvironment modifiers, antivascular agents, and the new generation of immunotherapy, comprise different chapters of this long journey. Each, guided by new findings, discoveries, and dominant thinking of forefront thinkers of cancer medicine field. Each, celebrated with joy, and tarnished by disappointments. Each era characterized and shaped by a different type of understanding of the underlying mechanism of neoplastic transformation.

We have reached a point in this journey, that a deep and true understanding of the underlying mechanism of neoplastic transformation is needed more than ever before. Such understanding would revolutionize cancer therapy, and take our despairs away.

Breakdown of the fine interplay of the second law of thermodynamics with the living cell, and its different manifestations in numerous disease states, most specifically cancer, alongside advances in single cell sequencing, evolutionary biology, mathematical biology models, nanotechnology, and artificial intelligence, would offer us a unique and historical opportunity to turn cancer into one of the many chronic disorders.