Drug Treatment Coupled with X-Ray Irradiation to Determine Cancer Cell Kill

Chandler Brock Author

08/03/2020 Added

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Researched various drug treatment options, coupled with x-ray irradiation, to be used for brain cancer (GBM).

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[00:00:01.232]My name is Chandler Brock
[00:00:02.457]and the research that I conducted this
[00:00:04.395]summer was over "Drug Treatment Coupled
[00:00:07.084]with X-Ray Irradiation to Determine
[00:00:08.949]Cancer Cell Kill".
[00:00:13.962]A little bit about me. I am from Cozad, NE
[00:00:16.690]and am going to be a senior this fall,
[00:00:19.559]majoring in Biological Systems
[00:00:21.062]Engineering with an emphasis in Biomedical
[00:00:23.435]Engineering.
[00:00:27.544]Some background on the research.
[00:00:29.642]Cancer is the 3rd leading cause of death
[00:00:31.563]in the world. Gene mutations promote
[00:00:34.738]cancer cells and is why they exist.
[00:00:37.487]Glioblastoma, or GBM, is an aggressive
[00:00:40.585]brain cancer and is what I was primarily
[00:00:43.660]studying. Better treatments must be found
[00:00:47.534]and x-ray irradiation coupled with drug
[00:00:50.241]treatment is the route
[00:00:52.112]that I was researching.
[00:00:54.345]Due to COVID-19, my lab work was done
[00:00:56.996]remotely from home.
[00:01:01.550]The objective: To understand the optimal
[00:01:04.232]treatment to maximize long-term cell kill.
[00:01:06.825]I hypothesize that the cancer cells
[00:01:09.725]treated with the correct drug will be more
[00:01:12.185]sensitized to radiation and experience
[00:01:14.266]better long-term cell kill than the cancer
[00:01:16.696]cells that are not
[00:01:17.799]treated with the correct drug.
[00:01:22.670]The methods that I used. I researched
[00:01:24.837]various drug treatment options and
[00:01:27.119]cancer data from sources such as
[00:01:29.185]The Cancer Genome Atlas, or TCGA, NCBI,
[00:01:34.093]PubMed, or the journal, Nature-along with
[00:01:40.108]the others listed there [and then some].
[00:01:42.528]The cancer drugs that I researched were
[00:01:47.326]these six. To start things off, AZD2461 is
[00:01:53.357]a PARP inhibitor and I'll talk about the
[00:01:56.117]different genes that they inhibit in the
[00:01:58.207]next few slides. I looked at KU55933,
[00:02:01.843]E3330, NU7026, NU7441, and Wortmannin.
[00:02:10.469]Wortmannin inhibits ATM and DNA-PK at
[00:02:16.057]high concentrations.
[00:02:21.430]The PARP gene. PARP helps to
[00:02:24.473]repair damaged DNA and blocking PARP
[00:02:27.911]prevents cancer cells from repairing
[00:02:30.066]their DNA, which is why it's very vital in
[00:02:32.976]cancer research. So a substance that would
[00:02:35.966]block this PARP enzyme is called a PARP
[00:02:38.443]inhibitor. PARP stands for poly (ADP-
[00:02:44.125]ribose) polymerase.
[00:02:49.148]The ATM gene. It plays a critical role in
[00:02:52.906]the development of the nervous system,
[00:02:54.716]provides instructions for making proteins
[00:02:56.870]in the nucleus, helping control cell
[00:02:58.839]division. It assists in recognizing
[00:03:01.418]damaged or broken DNA and activates
[00:03:04.309]enzymes that fix broken DNA. So because of
[00:03:08.019]this central role in cell division and DNA
[00:03:10.295]repair, it is of utmost interest in cancer
[00:03:12.876]research.
[00:03:17.094]The APE1/Ref-1 gene is a multifunctional
[00:03:21.780]enzyme involved in BER, or base excision
[00:03:25.780]repair. It gets the Ref-1 name because
[00:03:29.341]it's a reductive activator of many
[00:03:31.331]transcription factors. [It] maintains
[00:03:34.037]cellular homeostasis via activating
[00:03:36.678]transcription factors that regulate
[00:03:39.226]physiological processes and levels of
[00:03:41.626]reactive oxygen and nitrogen species.
[00:03:44.581]It acts as a 'hub-protein' that controls
[00:03:47.111]pathways important for cell survival.
[00:03:51.802]The DNA-PK gene is a DNA dependent protein
[00:03:57.411]kinase. It functions in double strand
[00:04:00.533]break repair, or DSB. It is a critical
[00:04:04.298]component of the response to damage
[00:04:06.043]and it fixes DNA by tethering damaged DNA.
[00:04:14.339]So the first drug that we're looking at,
[00:04:16.293]AZD2461, is currently in the clinal trial
[00:04:20.841]stage by AstraZeneca. A primary outcome is
[00:04:26.520]to determine the maximum tolerated dose of
[00:04:28.906]the drug via collection of various tests
[00:04:31.777]such as vital signs. A secondary outcome
[00:04:34.364]is to evaluate the pharmacodynamic
[00:04:36.794]response after treatment as the change in
[00:04:39.405]PARP inhibition in the cells.
[00:04:42.058]KU-55933 blocks the activation of Akt,
[00:04:47.988]which is a critical player in cancer
[00:04:49.778]development. When inhibiting ATM, Akt is
[00:04:54.653]blocked and the cancer cells undergo
[00:04:56.429]apoptosis. Essentially, it inhibits cancer
[00:04:59.671]cell proliferation by inducing G(1) cell
[00:05:02.413]cycle arrest. And here is a graphic of the
[00:05:07.715]KU-55933 [drug] as well as well as
[00:05:10.454]NU-7441 which I'll talk about here in the
[00:05:13.483]next couple slides.
[00:05:17.207]So the next drug, E3330, is an APE1
[00:05:22.133]inhibitor and it has detrimental effects
[00:05:25.262]on cancer cell viability. It is also shown
[00:05:31.051]to reduce the growth of pancreatic cancer
[00:05:33.624]cells.
[00:05:36.993]NU7026 inhibits DNA-PK and also proves to
[00:05:42.027]be a powerful strategy in overcoming
[00:05:43.960]therapeutic resistance when treating
[00:05:45.763]cancer cells. [It is] an ATP-competitive
[00:05:48.758]and highly selective inhibitor of DNA-PK,
[00:05:51.958]with a 60-fold greater potency for DNA-PK
[00:05:55.539]compared to PI3Ks.
[00:06:02.542]NU7441 inhibits DNA-PKs as well and
[00:06:07.737]enhances radio sensitivity by delaying DSB
[00:06:10.559]repair. A combination of IR and NU7441 has
[00:06:18.399]a modest effect on DSB, double strand
[00:06:21.539]break repair, in cells deficient in DNA-PK
[00:06:24.890]activity. The drug enhances the
[00:06:28.248]synergistic antitumor effect in NPC cells
[00:06:31.673]when applied in combination with
[00:06:33.539]irradiation by impairing DSB repair,
[00:06:36.860]prolonging cell cycle progression and
[00:06:39.553]activating the cell cycle checkpoints,
[00:06:42.261]which suggests that a DNA-PK inhibitor
[00:06:44.462]is a potential radio sensitizer in NPC.
[00:06:50.730]Here's another graph, or results, of the
[00:06:54.923]drug. And as you can tell, when the
[00:06:57.589]concentration increases, the plating
[00:07:00.262]efficiency decreases. And here it is
[00:07:03.669]when it's coupled with x-rays as well as
[00:07:06.054]carbon.
[00:07:12.159]So Wortmannin, the last drug that I looked
[00:07:14.459]at, is the most used ATM inhibitor (along
[00:07:17.068]with caffeine). However, it's neither
[00:07:18.971]specific nor useful in vivo, which has
[00:07:21.673]fueled an interest in identifying more
[00:07:23.995]specific and potent inhibitors
[00:07:26.411]and resulted in the recent
[00:07:28.192]identification of KU55933 which
[00:07:31.056]we just discussed previously.
[00:07:34.305]So the results. Most of the drug
[00:07:36.444]treatments that were studied, when coupled
[00:07:38.477]with x-ray irradiation, seemed to have
[00:07:40.651]good results. Inhibiting certain genes and
[00:07:42.853]then using radiotherapy proves to be one
[00:07:44.811]of the best treatment options for brain
[00:07:46.683]cancer. Furthermore, KU-55933, E3330,
[00:07:52.638]NU7026, and NU7441 with x-ray irradiation
[00:07:59.563]seem to be efficient strategies in
[00:08:01.488]treating GBM.
[00:08:04.662]Some future directions. I would like to
[00:08:07.126]conduct this research in a lab using these
[00:08:09.342]drugs. I also plan on attending medical
[00:08:12.790]school, so I could use this knowledge
[00:08:14.804]to help further me in my career in the
[00:08:18.338]future.
[00:08:20.886]Acknowledgments: I would like to thank
[00:08:22.863]Dr. Kievit and my lab mates.
[00:08:25.509]And here are my resources. Thank you
[00:08:27.812]for watching my video.

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Drug Treatment Coupled with X-Ray Irradiation to Determine Cancer Cell Kill

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