New Concepts in Cancer Therapy with Combined Radiation and Drugs

his article focuses on new concepts in drug development related to radiation oncology and describes opportunities uniquely available to radiation sciences that reach into aspects of our world that broadly relate to human health, concluding with concepts that are beyond the more common approaches to human healthcare in the developed world.

Key Takeaways:

• Radio-chemotherapy in the era of precision medicine offers unique uses for drugs by targeting pathways such as DNA repair so that a drug might work in combination with radiotherapy when it has little efficacy by itself.
• Radiation dose should consider both the physical dose (Gray or Gy) and the molecular and biological perturbations produced by radiation. Radiation-inducible targets can make a drug effective in cell killing after radiation when it was not effective before.
• Radiation is not just “radiation,” as the type of radiation (X-ray, particles, systemically targeted radionuclide therapy [TRT]), dose, and fractionation produce different changes. Thus, the pharmacokinetics and pharmacodynamics of radiation delivery can be exploited.
• Applications of radiation science extend beyond cancer biology to space exploration, energy policy, disaster response, and healthcare to the underserved. Surprisingly impactful opportunities exist for industry.

The obvious differences between radiation biology and chemotherapy biology may be discounted since combinations of these therapeutic approaches can be complementary and over-expectations of outcome from either approach alone can lead to inappropriate optimism or pessimism. Considering the relationship between the extent of in vitro cell killing (in logs) and drug dose, one generally needs to use concentrations well beyond those achievable in the clinic to kill 1 log (down to 10 percent survival), while clinically achievable single or multi-fraction radiation doses can produce many logs of killing (down to 0.1 percent). With few exceptions beyond lymphomas, drugs rarely eradicate established macroscopic disease while radiation alone and in combination with chemotherapy can provide local control of sizeable lesions. Repeated exposure to drugs usually results in drug resistance or selection of a resistant clone from the original population while repeated exposure to X-rays rarely leads to the development of a cell that has a significantly different radiation survival curve; however, cells do remember the radiation (discussed below). Modern cancer therapy involves mechanisms of tumor response beyond cell killing, but the differences in how cells or tumors “see” radiation and drugs differ and likely matter clinically.

Radiation Therapy

Radiation therapy itself is often lumped as “radiation” without distinguishing how it is delivered and what it is physically. Radiation largely kills cells by causing unrepaired DNA damage with the extent and type of the damage and the ability to repair it dependent on the size of the dose, the microenvironment (particularly hypoxia that leads to radioresistance), the cell’s survival pathways (DNA repair, stress response, etc.), stage of cell cycle, and “stemness.”

Radiation therapy is generally given using X-rays from linear accelerators, which now have superlative technology for target localization and treatment delivery with image-guided radiotherapy. Charged particle radiotherapy ranges from protons to heavier particles such as carbon. By having charge and mass, these particles will give up a large proportion of their energy in a sharply defined Bragg peak at the target with little dose beyond the peak. The dose beyond the peak does need to be taken into account as it can impact normal tissue. The charged particles produce different patterns of energy deposition compared to X-rays (called linear energy transfer, LET) and a larger relative biological effectiveness (RBE). That means, Gray (Gy) for Gy-charged particles with RBE up to 4 are much more effective. Radiation can also be delivered using systemically administered targeted radionuclide therapy (TRT) in which the radiation dose can be highly concentrated based on tissue/tumor uptake, an example being Radium-223 for prostate cancer. Notably, NCI TRT workshops have emphasized the critical importance of dosimetry to optimize the utility of systemic TRT.

Radio-Chemotherapy

Most commonly, radiotherapy and chemotherapy are used simultaneously, often called radio-chemotherapy. Combinations are based on pre-clinical models, clinical observation, and some empiricism, combining drugs that work with radiation that works. Systemic toxicity of the drugs and toxicity of radiation to local normal tissue generally limits treatment, thus the potential benefits of carefully tailored radiation. In the era of precision medicine and molecularly-targeted chemotherapy, combinations often are tested using specific agents that can enhance DNA damage (by inhibiting repair) or by preventing cell survival by inhibiting a survival pathway.

What is now emerging as a completely new paradigm for radiation therapy is defining dose in physical terms with radiation dose (Gy) and also in the biological perturbations produced by radiation dubbed “Shades of Gy” in an NCI workshop to indicate that physical and biological definition of dose is a potentially unique way to use radiation. The initial observation that radiation dose and schedule can cause an adaptation that can be targeted after radiation came from an experiment at our NCI laboratories. Three tumor types—brain, prostate, and breast—were irradiated in vitro and in vivo with 2 Gy per day for five days (multi-fraction or MF) or 10 Gy in a single dose (SD) and gene expression was analyzed post-treatment at multiple time points up to 24 hours. The adaptation following the MF showed more changes in gene expression and a more stable persistence. Interestingly, immune response was the pathway most upregulated. Further detailed studies conducted by our laboratory in prostate cancer cell lines demonstrated that adaptation after MF was greater than after SD including induction of other mRNA, microRNA (miRNA) and long-non-coding RNA (lncRNA), phosphoproteins, and metabolites. Changes were seen in normal endothelial cells.

Two recent proof-of-concept studies by Iris Eke and colleagues in our laboratory demonstrated that a survival pathway (AKT-mTOR) induced by MF can be targeted post-irradiation but not pre-irradiation. In intriguing studies, Eke demonstrated that adaptation by upregulation of integrins can be targeted in cells that survive and regrow two months following radiation. In data not yet published, while there was more adaptation immediately following MF (1 Gy x 10) compared to SD (10 Gy x 1), the converse was true at cells examined two months later. This phenomenon has applications for cells that might persist or recur following radiation (and likely drugs as well). We are now investigating the mechanism of the adaptation and how to select targetable pathways.

The importance of radiation dose and fractionation is relevant for immunotherapy. Claire Vanpouille-Box and our collaborators Silvia Formenti and Sandra Demaria at Weill-Cornell are leaders in using radiation therapy to enhance immunotherapy with immune checkpoint inhibitors and in exploiting the abscopal effect by which treatment to one tumor induces a therapeutic response to tumor metastases through an immune response mechanism. In a breast cancer model, they have demonstrated a “sweet spot” for radiation dose and fraction (8 Gy x 3) for successfully treating the primary tumor and inducing the abscopal effect. The mechanism involves the processing of damaged DNA to the right amount to stimulate an interferon response.

As noted above, molecular changes have been observed with MF and SD for endothelial cells in culture. My laboratory is involved in studies of circulating biomarkers for assessing normal tissue injury following whole-body irradiation as would be encountered following accidental or intentional exposure. Molykutty Aryankalayil has demonstrated that RNA biomarkers are potentially useful with further work on various circulating RNA species and exosomes. Work is ongoing to identify circulating organ-specific biomarkers that might have relevance for clinical radiotherapy.

In Summary

There is great potential for the use of radiotherapy as “a drug” by understanding and exploiting changes that are induced by various forms of radiation. In essence, it is understanding the pharmacokinetics and pharmacodynamics of radiation. Radio-chemotherapy will likely induce similar exploitable changes. This overall approach using the ability to physically focus radiation and induce susceptible targets, dubbed “focused biology,” was first proposed sixteen years ago. However, for this approach to become useful for cancer treatment, clinicians and scientists must recognize that tumors and normal tissues respond to radiation, and it behooves us to understand what these tissues “see” and how they adapt.

Regarding the DIA commitment to “improve health and well-being worldwide,” the role of radiation sciences is best considered in potential broad societal contributions. Colleagues from the NCI Radiation Research Program and CERN (European Organization for Nuclear Research), while considering the various frontiers and crossroads available for important contributions, came up with the idea of a “Radiation Rotary” as there are a number of intersecting crossroads. Radiation science and its effect on humans impacts cancer care, diagnostic imaging, space exploration, nuclear war/terrorism, and energy policy (resulting from environmental climate change). Relating specifically to patient outcomes worldwide, an enormous number of people in World Health Organization defined Low- and Lower- Middle-Income countries are without effective cancer care. It is projected that 70 percent of cancers will occur in the developing world with a staggering shortage of technology and expertise. Not surprisingly, geographically remote populations in the US and other developed nations, who are often the indigenous populations, have similar lack of access to care. Addressing cancer care as focal point for non-communicable diseases (NCDs), and demonstrating the link between NCDs and infectious diseases is the mission space of the International Cancer Expert Corps (ICEC), a non-government not-for-profit (of which the author is an advisor). Addressing these healthcare system shortages not only addresses major global inequality but also provides an opportunity for expanding health and economic opportunity, improved understanding of the roles of infectious diseases, genetics and the microbiome on cancer etiology, and establishing true mutually beneficial global partnerships.

Adapted from a presentation to FNIH Biomarkers Consortium: Molecular Radiation Oncology, November 5, 2018.

References available upon request.