1.1. Cancer Treatments Discovered over the Last 70 Years
One could historically consider the birth of the modern era of cancer therapeutics to be the serendipitous discovery of nitrogen mustard during the second world war [1
]. The surprising shrinkage of lymph nodes of a lymphoma patient some 77 years ago opened a new chapter and gave birth to the modern era of cancer therapeutics [2
]. Behind this, was the keen observation of scientists, following accidental explosion of mustard gas barrels on the way to Europe from America [3
]. The dedication and hard work of Karnofsky and the clinical genius of Farber were the building blocks for developing the field of oncology [4
The thinking at that time was that nitrogen mustard could kill the rapidly dividing malignant lymphocytes. This prompted the need for understanding the mechanism of action, dosimetry, and minimum duration of treatment [6
]. Shortcomings and relapse started the process of thinking of drug resistance and the need to add other cytotoxic agents to treatment regimen [8
]. With parallel advances in other fields such as chemistry, biochemistry, and biology, new opportunities arose [9
]. This brought with it new challenges and bigger questions. Some of those questions included, why did not all the malignant cells die? How could malignant cells grow in the presence of a cytotoxic agent? Why one cytotoxic agent works in one malignant disorder, and not in another? What dose and duration would lead to the best outcome? What should we do to minimize side effects?
As knowledge regarding intracellular pathways grew, awareness of mechanism of action was taken to a higher level. Discovery of fluorinated pyrimidines during Heidelberger’s experiments on hepatoma cell lines in 1950s [10
], brought 5-fluorouracil (FU) into the cancer clinical arena [11
]. Indeed, as of today, 5-FU remains a major component of colon cancer treatment protocols, more than 60 years after that discovery [11
The concept of multi-agent chemotherapy was born following better understanding of intracellular communication networks, as well as cell growth and division [12
]. The National Cancer Institute’s initiative of exploring naturally occurring compounds in the treatment of cancer, led to the generation of an archive of more than 30,000 compounds on the shelves of NCI. A significant number of the agents currently used in the treatment of cancer come from that source [13
]. Another serendipitous discovery, this time of platinum in the 1970s by Einhorn, turned the catastrophic and tragic history of testicular cancer into a unique success story [14
]. Later on, and as of today, almost 50 years after that date, different platinum derivatives are the cornerstone of head and neck, lung, and gynecological cancer treatment protocols [15
]. Another contribution of platinum discovery was a wake-up call that, perhaps there are other platinum-like agents for other cancers that we have not yet tried.
Radiation therapy also came to be recognized as another cytotoxic therapy, and through time found its way into cancer treatment protocols. Its surprisingly positive effect in Hodgkin lymphoma in 1960s expedited this process [16
]. Discovery of the potential synergistic effects of radiation therapy and chemotherapy, together, generated a foundation that led to the combination of chemo and radiation therapy in the treatment of head and neck, lung, and brain cancer, as well as lymphoma treatment protocols [17
The discovery of double helix DNA by Watson and Crick in early 1950s generated the next footstep in the pathway of the evolution of cancer therapeutics thinking. Cancer was soon regarded as a disorder of genes. Inactivating mutations of tumor suppressor genes and activating mutations of oncogenes, and the resulting distortions of cellular signaling pathways gave further support to that thinking [20
]. The discovery of carcinogens, specifically cigarette smoking, opened the door on research on their interaction with human genome [21
]. Environmental factors, cancer prevention, screening, and early detection, followed in the footsteps of the above mentioned findings, and contribute to our present national health and cancer treatment policy guidelines.
1.2. Chemo- and Targeted-Therapies Co-Exist in Today’s Cancer Clinic
The next step in the evolution of cancer therapeutics was guided by the discovery of growth promoting and inhibitory pathways, cell cycle kinetics, including cyclin dependent kinases, oncogenes, tumor suppressor genes, gene regulatory machineries, and nuclear receptors. This was followed by discovery of epigenome, and micro-RNA network [22
While still using chemotherapy in cancer clinic [8
] and oncolytic viral vector-mediated cytotoxic therapy in clinical trials [23
], we have been treating our cancer patients with a vast array of targeted therapeutic agents [24
]. These agents include tyrosine kinase inhibitors [25
], therapeutic antibodies [26
], microRNA therapy, cytoreductive gene therapy, and gene editing for restoration or destruction of deregulated genes [27
], epigenome modifiers [30
], and proteosome inhibitors [31
]. With an ever-increasing arsenal of cancer therapeutics and their rapid appearance in the cancer clinic, there has come significant refinement, and an explosive expansion of the number of clinical trials [32
1.3. Immunotherapy Has Begun to Appear in Upfront Regimens
Publications about cancer treatment have recently started to move away from chemotherapy, and focus more on targeted therapeutics agents, and cell-based immunotherapy, tumor vaccines [33
], and most recently checkpoint inhibitors as the new generation of immunotherapy in upfront regimens [34
]. The history of immunotherapy for cancer goes back more than one hundred years. The thinking that the immune system could eliminate or prevent cancer was described in the work of some investigators who inoculated themselves with cancer cells of their patients [36
]. Bacillus-Calmette-Guerrin (BCG) vaccination was also used to boost the immune system against cancer. Indeed instillation of BCG into the urinary bladder of patients diagnosed with transitional cell carcinoma of urinary bladder following surgical resection is still in use. Herpes simplex virus-based oncolytic immunotherapy is now applied in European cancer clinics for unresectable advanced stage of melanoma [37
Around one in six cancers are thought to have their roots in infection. Some of the well-known examples include hepatitis B and C induced hepatocellular carcinoma, human herpesvirus-8 induced kaposi sarcoma in acquired immunodeficiency syndrome, epstein-Barr virus induced Burkitt lymphoma in sub Saharan Africa, human papillomavirus induced carcinoma of cervix and oral cavity and Helicobacter Pylori induced gastric maltoma. Vaccination against specific human papillomavirus serotypes has significantly reduced the incidence of squamous cell carcinoma of cervix. Because of immune dysregulation, low level of tumor antigen presentation, cross reactivity with self-antigens, and poor immune response among many other pitfalls, vaccination against the vast majority of malignancies has continued to face major challenges. High dose IL2, with or without lymphokine or anti-CD3 activated killer cells in the treatment of melanoma in 1990s led to minor response with major and life threatening toxicities. Alfa-interferon showed similar results and had similar problems.
Immunotherapy for cancer came into focus around 30 years ago, with mononuclear cells from the peripheral blood, activated ex vivo, and then re-infused into patients with tumor. This treatment failed to achieve long-term responses [38
]. Our frustration with the old generation of immunotherapy in the 1990s has most recently been replaced renewed optimism based on more recent results with checkpoint inhibitors, such as PD-1 antagonists [39
]. This is the result of a more sophisticated understanding of immune regulatory pathways, since the original studies of T-cell regulation by immunologists. In essence, unleashing the immune response to tumor cells and their antigens has dramatically improved response rate and survival in a diverse group of malignancies associated with poor prognosis, including malignant melanoma [40
]. Currently, there are seven approved check point inhibitors that target CTLA4, PD-1, and PD-L1 by the US Food and Drug Administration for cancer treatment ranging from non-small cell lung cancer to Merkel cell carcinoma [41
]. Unfortunately, they have limited efficacy in patients with central nervous system (CNS) tumor glioblastoma or brain metastases [42
]. CAR-T and BiTE are also among recent strategies in this regard [43
]. These are among the most sophisticated technologies to kill cancer cells.
The limits of immunotherapy arise from major similarities between normal cells and cancer cells, especially cancer stem cells, with little differences of their surface antigens. Cancer stem cells could easily repopulate the tumor following escape from current immunotherapeutic measures. However, the new generation of immunotherapy is a significant step in the evolution of cancer therapy, simply because we are recruiting the body’s natural defense to fight cancer. We are also trying to avoid toxicities associated with chemotherapy and radiation therapy, including generation of destructive mutations originating from the therapies themselves [44
]. However, this strategy for cancer therapy has limitations and will not likely become a panacea for cancer therapy because of poor overall cancer immune responsiveness, and the relatively immune-privileged milieu of the CNS [45
]. We have already started to face toxicities and relapse following such treatment measures.
1.4. Current Limitations of Anti-Angiogenesis Therapy
The role of blood vessels in tumor progression has been investigated for more than a century [47
]. Folkman’s hypothesis about the essential role of angiogenesis in solid tumor development [48
] and discovery of angiogenic factor VEGF [49
] initiated enthusiasm for anti-angiogenesis therapy. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody, is a major anti-angiogenesis drug in clinical use [50
], to treat some devastating types of cancer, including non-small cell lung carcinoma, glioblastoma multiforme, ovarian cancer, metastatic colorectal cancer, metastatic breast cancer, and metastatic renal cell carcinoma. This has led to transient tumor control and palliation of clinical symptoms [51
]. However, the attempts to “starve” and turn a tumor into a “dormant” disease have proven to be a failure as far as improvement of overall survival is concerned [52
]. Once again, cancer evolves because of selection pressure favoring an emerging cellular phenotype where neoangiogenesis is not a rate-limiting issue.
Although most of the blood vessels in tumor are derived from angiogenesis, the leaky blood vessels in tumors, namely vasculogenic mimicry (VM), support rapidly growing tumors. They arise from tumor cells that have undergone endothelial trans-differentiation. With this process, neoplastic cells take on endothelial features and form abnormal blood vessels to help supply the tumor. This is an important part of tumor vascularization associated with cancer progression [54
]. Current anti-angiogenesis agents work on suppressing normal cells to inhibit formation of blood vessels in tumor, but not on tumor cells to inhibit VM [62
] or migration along the preexisting vessels of the host organ, namely vessel co-option, regarded as an alternative tumor blood supply [63
]. The other reason for lack of survival improvement by anti-angiogenic therapy is failure to appreciate cancer’s capability to change, from high proliferation reliant on vascularity, to high invasion and/or avascular single cellular states triggered by the pressure of “starvation” therapy [64
]. Starvation is a selection force in cancer evolution that pushes cancer to shift to other successful tactics to cope with the ever-changing tumor microenvironments of over-growth, hypoxia, and low pH. Anti-VM agents used to achieve vascular normalization, not only might improve anti-angiogenic therapies through synergistic and/or additive effects, when coupled with current anti-angiogenic therapies, but could significantly improve survival as well [66
]. Recent efforts to identify anti-angiogenic compounds from natural products based on their effects on other essential tumorigenic pathways [68
], and development of human fibulin-3 variant with dual antivascular function [69
] beside other tumor-suppression effects in brain tumor model [70
], are promising new directions in the evolution of cancer therapy.
1.5. Therapeutic Strategies Based on Targeting Cancer Stem Cells
Recognition of cancer as a disease of genes and dysregulated molecular pathways of cell growth guided the development of targeted therapies. Identification and characterization of a small population within neoplastic cells, described as cancer stem cells (CSC), and their role in cancer evolution and cancer recurrence [71
] has guided the recent development of a new generation of targeted therapy against this cancer cell population. In the past decade, therapeutic agents have been developed to target CSC surface markers, crucial developmental signaling pathways for stem and progenitor cell homeostasis and function, such as the Notch, WNT, Hedgehog, and Hippo signaling cascades, as well as CSC niche and differentiation therapy. These approaches are currently at different stages of clinical development. Some have achieved promising results in certain malignancies, such as thyroid cancer and refractory desmoid tumors treated with γ-secretase inhibitors. For refractory acute myeloid leukemia (AML), agents that promote β- catenin degradation; for basal cell carcinoma, hedgehog inhibitors; and for SHH-subtype medulloblastoma and newly diagnosed AML, SMO inhibitors have been tried [75
]. One has to wait for maturation of data and further developments in this field, given the high toxicity experienced by patients and potent anti-tumor activity in some preclinical models, which have failed to be reproduced so far in clinical studies.