Figure
1 Changes in overall survival across multiple cancers between 1971 and
2011.
Credit: Cancer UK; from (2) Cancer Research UK. (2019, July
19). Cancer survival for common cancers. Retrieved October 14, 2020, from
https://www.cancerresearchuk.org/health-professional/cancerstatistics/survival/common-cancers-compared.
Pancreatic Ductal Adenocarcinoma (PDAC) is currently one of
the most difficult to treat types of cancer, with an overall five-year survival
rate of only 9%, and an increase in death rates between 2012 and 2016 (1).
There has been very little progress in PDAC treatment efficacy despite decades
of research. This in in contrast to many other cancer types which have seen
significant improvements in available treatment options, as seen in figure 1
(2). This sets PDAC apart as an area of particular importance for developing
effective treatment strategies to try to overcome many of these
difficulties.
PDAC is a disease that develops from non-malignant
precursor lesions that progress slowly, often taking years to adapt a
metastatic phenotype and developing into an advanced stage invasive
cancer(3,4). At this point, disease progression becomes much more rapid,
contributing to the poor survival rates (5). This pattern of progression is
perhaps the largest hurdle that clinicians need to overcome, as during this
long period of growth and development most patients experience no symptoms at
all, making early detection or treatment next to impossible (6). Because of
this, when most patients are finally diagnosed the disease is already at an
advanced stage, with less than 20% of PDAC diagnoses shown to be surgically resectable
due to tissue invasion or metastasis (7). This puts an emphasis on the need for
non-surgical treatment options, but these treatments have many of their own
problems.
PDAC is characterized by a highly desmoplastic and fibrotic
microenvironment surrounding the tumor core, packed with immune cells and
cancer-associated fibroblasts that produce large amounts of extracellular
matrix factors (8). This microenvironment serves to isolate the tumor core,
which is the reason why most patients are asymptomatic. However, it also serves
as very effective barrier for chemotherapy treatments (9), and because most
drugs have difficulties reaching the tumor core they are developed to act on,
even the most promising drugs will inevitably prove ineffective. Currently, the
most effective chemotherapeutic agent is FOLFIRINOX, which is a combination of
oxaliplatin, irinotecan, fleurouracil, and leucovorin that has been shown to
increase overall survival by 11.1 months (10). However, this efficacy comes
with a price of high toxicity, with serious side effects including severe
fatigue, sensory neuropathy, anemia, thrombocytopenia, and diarrhea. Because of
the toxicity of FOLFIRINOX, many patients are not able to receive this
treatment due to poor health. As a way of providing some treatment to patients
who cannot withstand the toxicity of FOLFIRINOX, gemcitabine along with
albumin-bound paclitaxel (nab-paclitaxel) can be administered to increase
overall survival by 8.5 months with a much better safety profile (11, 12). However,
these patients have to settle for suboptimal therapy, so there is certainly a
need to find a way to increase the efficacy of chemotherapy in these patients
without increasing toxicity.
Figure 2 Visualization of microbubble forces in sonoporation.
From (14) Fan, Z., Kumon, R. E., & Deng, C. X. (2014). Mechanisms of microbubble-facilitated sonoporation for drug and gene delivery. Therapeutic delivery, 5(4), 467-486.
doi:10.4155/tde.14.10
To address this issue, studies are being performed using
sonoporation in conjugation with less toxic PDAC treatments including
gemcitabine and paclitaxel to try and elicit a more effective response.
Sonoporation involves the use of microbubbles that, along with ultrasound
stimulation, can result in temporary formations of small pores in the nearby
cells (13). These pores are created by the forces generated by the microbubbles
as they are manipulated by the ultrasound waves (14). The different types of
forces can be seen illustrated in figure 2. The idea behind using this
technique is that creating these pores will facilitate drug entry into cells,
both increasing efficacy and reducing the required dose.
Additionally,
sonoporation can be localized to very specific areas depending on ultrasound
administration, and the process is very safe, as microbubbles have been used
for many years as a contrast agent in ultrasound imaging (15).
Figure 3 Overall
survival increases seen in patients treated with gemcitabine +
sonoporation.
From (17)
Dimcevski, G., Kotopoulis, S., Bjånes, T., Hoem, D., Schjøtt, J., Gjertsen, B.
T., . . . Gilja, O. H. (2016). A human clinical trial using ultrasound and
microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer. Journal of Controlled Release, 243,
172-181.
doi:https://doi.org/10.1016/j.jconrel.2016.10.007
Initial tests of this technique applied in orthotopic
xenograft mouse models of PDAC demonstrated a significant decrease in tumor
volume compared to normal gemcitabine treatment alone, as well as an increased
survival rate in the mice treated with sonoporation (16). These results were
very promising, and prompted a shift to human clinical trials to understand if
sonoporation could result in more effective treatments without toxicity.
Testing sonoporation + gemcitabine chemotherapy in patients with inoperable
pancreatic cancer proved quite successful. Median survival of patients was
increased from 8.9 months to 17.6 months, and patients were able to undergo more
cycles of chemotherapy. Many patients also experienced an overall decrease in
tumor volume (17). These results are very promising, and demonstrate the
potential utility of sonoporation in conjunction with chemotherapy as a means
of increasing treatment efficacy without putting the patient at a higher risk
of toxicity. However, much work remains to be done to determine the ideal
conditions to ensure the greatest efficacy increase while maintaining a safe
profile.
By Zeke Rozmus, A Master of Medical Science Student at the University of Kentucky
References:
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doi:10.1016/s1091-255x(00)80105-5
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Nomura, A., Saluja, A., & Banerjee, S. (2017). Microenvironment in determining
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International Association of Pancreatology (IAP) ... [et al.], 17(1), 7-12.
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treat? Therapeutic advances in
gastroenterology, 6(4), 321-337. doi:10.1177/1756283X13478680
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Desseigne, F., Ychou, M., Bouché, O., Guimbaud, R., Bécouarn, Y., . . .
Ducreux, M. (2011).
FOLFIRINOX versus Gemcitabine for
Metastatic Pancreatic Cancer. New England
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D. D., Ervin, T., Arena, F. P., Chiorean, E. G., Infante, J., Moore, M., . . .
Renschler, M. F. (2013).
Increased Survival in Pancreatic
Cancer with nab-Paclitaxel plus Gemcitabine. New England Journal of Medicine, 369(18), 1691-1703.
doi:10.1056/NEJMoa1304369
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V., König, A., & Seufferlein, T. (2016). Current Standard and Future
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44-49. doi:10.1159/000447739
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Sonoporation at a low mechanical index. Bubble
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Kumon, R. E., & Deng, C. X. (2014). Mechanisms of microbubble-facilitated
sonoporation for drug and gene delivery. Therapeutic
delivery, 5(4), 467-486. doi:10.4155/tde.14.10
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F., Dimcevski, G., Engjom, T., & Gilja, O. (2011). Transabdominal
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S., Delalande, A., Popa, M., Mamaeva, V., Dimcevski, G., Gilja, O. H., . . .
McCormack, E. (2014). Sonoporation-Enhanced Chemotherapy Significantly Reduces
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G., Kotopoulis, S., Bjånes, T., Hoem, D., Schjøtt, J., Gjertsen, B. T., . . .
Gilja, O. H. (2016). A human clinical trial using ultrasound and microbubbles
to enhance gemcitabine treatment of inoperable pancreatic cancer. Journal of Controlled Release, 243,
172-181.
doi:https://doi.org/10.1016/j.jconrel.2016.10.007
Very interesting article Zeke, I had no idea that Pancreatic Ductal Adenocarcinoma (PDAC) is currently one of the most difficult cancers to treat. You mention that sonoporation can lead to increased efficacy as well as lower dose. Would sonoporation need to occur every time that a patient receives chemotherapy and would that be prior to the chemotherapy or at the same time it is administered? I just was not sure how long the microbubbles keep the pores open for.
ReplyDeleteThis is a very interesting way of making a systemic therapy more targeted. I imagine this may also help with other cancers that have become drug resistant by increasing entry into cells. With the decreased doses needed with sonoporation are there less side effects to chemotherapy? I'm very interested to see if this method could be utilized across the board with chemotherapy to increase quality of life while undergoing treatment.
ReplyDeleteReally well written article Zeke. I like how you gave us the background information about PDAC and then described how sonoporation can help with the challenge of penetrating the tumor micro-environment. Is there any research investigating if sonoporation could be furthering metastasis? I wonder if the pores in the cancer micro-environment could contribute to the spread of "cancerous debris" throughout the body.
ReplyDeleteThis is the first time I have heard of sonoporation and it sounds really cool and effective method to deliver drugs. Is the immune cells and fibroblast barrier that surrounds the tumor disrupted due to the sonoporation? It would interesting to dig deeper into the role of tumor microenvironment and how they are affected with different treatments.
ReplyDeleteVery interesting read. I work in a drug discovery lab where we not only develop new small molecule therapies, but we also investigate various ways of altering the drug delivery method to ensure the greatest efficacy and safety profile for the drugs. I had never considered physically altering the tumor microenvironment, in order to improve drug delivery, in this way. It's not really the way the drug is being delivered that's novel, but the preparation of the intended tissue. Like Bernardo, I too am concerned that the sonoporation technique could disaggregate some tumor cells and therefore become metastatic. I wonder if there is any data on this subject.
ReplyDeleteVery cool article. The idea that such a hard to treat cancer with low survival rates can have a treatment manipulated with sound waves is astonishing. As this is the most promising level of treatment for this particular case, do you think sonoporation would have uses elsewhere?
ReplyDeleteWow, this is a very innovative technique that sounds like it could be applied to a variety of aggressive tumors. I appreciate the background information on PDAC and how the extracellular matrix makes it difficult to penetrate with chemotherapy treatments. Do you know if there are other types of tumors that also exhibit this physical barrier? If so, I would imagine this treatment could be beneficial to various types of malignant tumors!
ReplyDeleteThis is my first time of hearing of sonoporation. It sounds like a fascinating and promising method to help in the treatment of PDAC. I think it is amazing that we are able to use ultrasound waves as a treatment instead of just using it for imaging. With such promise I did wonder why this technique has not been applied to other hard to treat and lethal cancers. More specifically could this be a way to treat other tumors throughout the body that are not operable, like in the brain? I also did not know about the tumors' micro-environment. Do other tumors in other areas of the body that are not operable have similar characteristics in their microenvironment?
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ReplyDeleteZeke, this is such an interesting topic. After reading about the success observed from using this innovative therapy in these patients, I am curious about some of the details of this trial. What stage were these patients in? Did their condition directly improve or only extend their life expectancy? What're the next steps in this research?
ReplyDeleteGreat read, thanks for sharing this novel approach. I have never heard of sonoporation before but I know a lot is being doing with ultrasound in medicine. I am curious to know what were some of the limitations of the study you shared. Also, I wonder if this also increase the quality of life for those patients. I know with chemotherapy, the patient is often debilitated from treatments, I wonder if this was true in the these patients.
ReplyDeleteWOW!!! This article is AMAZING!!! I actually lost my favorite Uncle June 28th this year to PDAC stage 2. It makes sense after reading this article on why the treatments were stopped due to his health issues, with the providers stating his heart just could not take it. The death time rate from diagnosis to the end was 5 months maxium. He did infact donate the biopsy to be researched to try to save someone else's life, in the search to help find a cure.
ReplyDeleteThis was very informative, I didn't know much of how PDAC was treated or of sonoporation being use to alter the permeability of membranes. But it does sound like a good way to help the effectiveness therapies in cases like this one.
ReplyDeleteThis blog was incredible and it is nice to know that some improvements are being made in the treatment of such a deadly cancer, such as this. I am curious about the method of administration and the drug delivery. I'm guessing the sonoporation technique involves either injecting the micro-bubbles directly into the identified cancerous tissue or there is some form of target sequence included into the molecular structure of the sonoporation compounds and can be given to the patient intravenously. It was also interesting that the effectiveness of the therapy can be partly determined by the use of ultrasound. This is the first time I have heard ultrasound being involved in a cancer therapy and did not realize how many uses it could have. I believe sonoporation could provide a great path for future research for oncologists/cancer biologists in the treatment of not only PDAC, but also every cancer.
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