Combination Therapy, Combating Cancer from Multiple Flanks

The Signing the National Cancer Act. President Richard Nixon signs the National Cancer Act on December 23, 1971. This is a formal setting with a row of senators visible and some other officials and dignitaries. Courtesy: National Cancer Institute, an agency part of the National Institutes of Health (ID 1935) / Linda Bartlett
The Signing the National Cancer Act. President Richard Nixon signs the National Cancer Act on December 23, 1971. This is a formal setting with a row of senators visible and some other officials and dignitaries. Courtesy: National Cancer Institute, an agency part of the National Institutes of Health (ID 1935) / Linda Bartlett

It has been almost 40 years since the “war on cancer” was formally declared with the launching of a program of this name by the U.S. congress in 1971. Since then, extraordinary advances have been made through the work of many private and public research and medical institutions worldwide. Their united efforts have focused on reaching a common objective: finding the best weapons against these devastating diseases that kill millions of patients every year worldwide.

In the last decades, evolution of our understanding of the nature and mechanisms behind cancer initiation and progression has been impressive. This progress has allowed not only advancements to conventional therapies such as chemotherapy and radiotherapy, but also the development of a wide variety of promising new ones such angiogenesis and checkpoint inhibitors. Yet, despite these advances only a few have entered the clinic with demonstrated efficacy in diverse patient populations, and for most forms of cancer the fight is not over.

Understanding the cancer battlefield
As members in the cancer community working to improve the outcomes of cancer patients we have joined the ongoing search of the next major advance in the fight against this hard enemy. Despite outstanding progress in the development of drugs to target tumor formation, growth and progression, most existing cancer therapies are only effective transiently, as cancer cells ultimately find a way to evade or resist the therapy. Understanding and tackling cancer relapse is necessary to effectively combat cancer drug resistance. This remains a challenging task since, as some have proposed, drug resistance is an evolutionary process. [1][2][3]

In addition, while grouped under a common name, cancer is not one disease but a collection of more than 100 diseases, each with unique genetic and histological characteristics that define its unique ability to grow and evade cancer therapies.

Cancer affects most organs and tissues, utilizing numerous and complex strategies to proliferate. These include but are not limited to, growth signaling, resistance to apoptosis (programmed cell death), immune surveillance evasion, tumor-promoting inflammation, or genome instability and mutation. [4][5]

The understanding that cancer is a consequence of mutations that affect signal transduction led to the development of “targeted therapy” directed at known enzymes or receptors whose activities are essential for the survival and proliferation of cancer cells. Examples of these therapies include anti-estrogens (tamoxifen) for the treatment of breast cancer, anti-androgens such as bicalutamide or nilutamide for the treatment of prostate cancer, inhibitors of different kinases such as imatinib (anti BCR-ABL) for the treatment of chronic myelogenous leukemia, afatinib (anti-HER2) for the treatment of non-small cell lung carcinoma, or vemurafenib (anti-BRAF) for the treatment of late stage melanoma, and antibodies targeting growth factor receptors such as EGFR (cetuximab), used in the treatment of head, neck and colorectal cancer [6][7][8][9][10][11]

Many others have also been studied and developed. While some of these, such as imatinib, have shown outstanding results, in most cases cancers evade treatment or develop resistance to these targeted therapies mostly due to tumor genome instability, acquisition of mutations, or the inability of the drug to target the specific mechanism of tumor progression. [11]

It is important to keep in mind that a tumor is not just a cluster of similar cancer cells but instead includes a heterogenous collection of resident and infiltrating host cells, secreted factors, and extracellular matrix proteins, collectively known as the tumor microenvironment. Tumor progression is extremely dependent and influenced by complex interactions within the cancer cells and other components of the tumor microenvironment, which has led to the investigation and development of therapies targeting its different components.

Evidence of this is seen in the number of immunotherapies that have been approved against widely studied inhibitory immune checkpoint pathways, which the tumor utilizes to “hide” from the host immune response, and which are currently utilized for a wide variety of malignancies showing durable clinical activities in a subset of cancer patients.

These include inhibitors of PD-1, such as pembrolizumab or nivolumab, inhibitors of PD-L1, such as atezolizumab, or inhibitors of the cytotoxic T lymphocyte antigen 4 (CTLA-4), such as ipilimumab. As of 2018, an estimated 43% of patients in the U.S. with cancer were eligible for treatment with checkpoint inhibitor drugs. Yet, as with targeted therapeutics, the results are not outstanding and the percentage of patients responding to single-agent checkpoint inhibitor drugs was 12.46%, including treatment of all tumor types. [13]

Combating cancer from multiple flanks
Cancer cells can evade cancer treatment through multiple mechanisms. In many cases, and due to the intrinsic diversity of tumor types, some tumors can naturally evade the functional blockage of a targeted drug. In other cases, drugs work temporarily but cancer cells become resistant using a variety of tools, including DNA mutations and metabolic changes that promote drug inhibition and and target alteration, or mechanism of cell death inhibition. [3]

Drug resistance in cancer is a multi-faceted process and as such, a successful strategy to combat cancer should not be one that tries to find and use that “magic bullet” against cancer but instead must focus on a combination of bullets that can effectively tackle the diverse cancer evolution and resistance pathways.

Novel genomic and computational tools are allowing us to better understand the complex mechanisms of this disease as well as develop novel screening diagnosis tools, which provides us with a tremendous opportunity to approach the cancer battle with a diverse and powerful set of weapons.

The future of cancer therapy relays on effective combination therapies. Now the key is to find that right combination.

References
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