How do we know if drugs are carcinogenic?

How do we know if drugs are carcinogenic?

We often see in the news headlines information of some drug being potentially carcinogenic or contaminated with substance that is potentially carcinogenic. But what that means and how do we test drugs for carcinogenicity?

Carcinogenicity testing of substances is preformed on nonhuman species at some quite high doses or exposure levels in order to predict the occurrence of tumorogenesis in humans at much lower levels.

Generally now we have good understanding of most of the mechanisms of chemical and radiation induced carcinogenesis. There is a list of know human carcinogens and you can find more details here

How do these carcinogenic substances work?

There are several mechanisms and theories of chemical carcinogenesis:

  1. Genetic (all due to some mutagenic event)
  2. Epigenetic (no mutagenic event)
  3. Oncogene activation
  4. Two-Step (induction/promotion)
  5. Multistep (combination of above)

Another way to classify them is based on the four major carcinogenic mechanisms:

  1. DNA damage
  2. Cell toxicity
  3. Cell proliferation
  4. Oncogene activation

How do we assess carcinogenicity?

The most simple approach is to design bioassays and evaluate if cancer occur or not in animal models. However, the complexity of oncology diseases require more sophisticated models and testing which is why now is taken in consideration time-to-tumor, pattern of tumor incidence, effects on survival rate and age of first tumor.

There are 3 aspects of organ responsiveness that have to be tested too:

  1. Those organs with high animal and low human neoplasia rates – In this group below animal cancer data in liver, kidney, forestomach and thyroid gland.
  2. Those organs with high neoplasia rates in both animals and humans – In this group are animal cancer models in mammary gland, hematopoetic, urinary bladder, oral cavity and skin.
  3. Those organs with low animal but high human neoplasia rates – There are lots of discussions about this group but some of the organs that are believed to belong here are prostate gland, pancreas, colon and rectum, cervix and uterus.

One of the limitations is lack of assessment of low neoplasia rates in both animals and humans.

As probably expected the carcinogenicity bioassays are the longest and most expensive part of toxicology studies. Often there are more controversial in terms of results.

According to the regulatory requirements 3 or 4 doses of the substance have to be tested to determine carcinogenicity. Usually are used 2 control groups of equal size and each group has minimum 50 animals of each sex. In the studies are normally used the maximum tolerated dose, the lowest dose and mid-dose, which often is geometric mean of the 2 other doses. The duration of the exposure to the dose is usually 2 years. Extended duration is often not suitable in rat and mice models because with the age it is increased the chance of spontaneous tumorgenesis.

While there is a room for improvement in carcinogenic studies there is lots of safety research going on before new therapeutics reach patients in later stages of drug development. Another important point to remember is that carcinogenicity of substances is not black and white and often more data is needed to determine if they really are carcinogenetic.


Drug Safety Evaluation

Published on 29 Nov 2019

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

Is it possible to have an anti-cancer therapeutic vaccine

Is it possible to have an anti-cancer therapeutic vaccine

There are many observations in melanoma lesions where the immune system is able to act against the tumours and usually this is a sign of a good prognosis. However, over time the balance is shifted in favour of the tumours.

All this suggests that vaccination for cancer immune therapy, which targets specific tumours could be a possibility in such cases. Current vaccination in cancer is primary a therapeutic intervention rather than prevention like the case with infections diseases. Preventive vaccination against cancer is not possible yet in humans.

But before we consider that type of vaccination there is a need to identify different vaccination strategies for cancer immune therapy and also identification of effective mechanisms used by the immune system.

Hybrid cell vaccination is one of these strategies that use the patient’s tumour cells as antigen and turn them into potent T cell stimulators by fusion with antigen-presenting cells (APCs) such as dendritic cells (DCs).

There are over 250 tumour-associated T cell epitopes derived from about 60 different proteins and majority of the antigens were identified for melanoma and are MHC class I-restricted. Some of these antigens identified in melanoma were later on identified in other tumours.

Cytotoxic T cells with specificity for differentiation antigens are not supposed to exist, as they should have been eliminated during the establishment of self-tolerance. However, they are observed in cancer patients and even healthy individuals. One potential explanation is that these antigen receptors might be of low avidity and in this case the T cells will also have too low efficiency to eliminate the tumour cells.

T cell epitopes specific to tumour cells would be ideal for immune therapy, however very few have been identified in cancer patients so far.


What kind of clinical data is available?

There are number of clinical trials using hybrid cell vaccination strategy that have shown promising results although the patient population were mostly stage IV. A vaccine prepared by fusion of autologous tumour cells with allogeneic activated B cells and given intracutaneously or intradermally have cause turmour response in 3 our of 13 patient with renal cell carcinoma and in 2 our of 16 patients with metastatic melanoma while 5 others had stable disease. Interestingly stable disease was maintained for more than 2 years for some patients.

Another study with allogeneic DCs and autologous tumor cells was completed with 17 patients with metastatic renal cell carcinoma. 4 of the patients had complete response; 2 patients – partial responses and 1 patient – mixed response. Some of the common side effects observed in these studies are: erythema at the sites of inoculation, some cases of fever and others of strong but temporal perspiration. Generally, toxicity is low.

While the results are promising more information is needed to support therapeutic use of hybrid cell vaccination.


Cancer Immune therapy: Hybrid Cell Vaccination for Cancer Immune Therapy

Published on 1 Oct 2019

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe


The role of microRNAs in human diseases

The role of microRNAs in human diseases

It is very common that microRNAs are overexpressed or inactivated in human diseases. The best approach in such cases is to either target the overexpressed microRNA to inactivate it or replace the inactive microRNA.

But let’s first review what is microRNA and what is their role.

MicroRNAs are small noncoding RNAs that are approximately 20-25 nucleotides in length. Most microRNAs are the same in different animal species, which underline the importance of microRNA in the evolution. The process of inactivating the microRNAs does not require perfect complimentary recognition of the target, because only the 6 to 8 nucleotides in the 5’ portion of microRNAs is sufficient to trigger interaction. Also single microRNA can regulate multiple mRNAs. More importantly the ability of microRNAs to influence entire network of gene involve in common cellular process provide great therapeutic opportunity.

miR-122 and hepatitis C

miR-122 is a microRNA expressed in liver, which helps hepatitis C virus (HCV) to replicate once it reaches the liver. It’s natural role in the liver is to regulate its metabolic functions – cholesterol homeostasis, fatty acids and lipid metabolism. miR-122 is conservative to HCV across all genotypes and subtypes. A clinical study using SPC3649, 15 nucleotide phosphorothioate oligonucleotide, has shown positive results in monkeys.

miR-33 and atherosclerosis

One of the potential mechanisms of eliminating LDL cholesterol involves efflux from the macrophages in atherosclerotic vascular lesions to circulating HDL, which will help to be excreted into the faeces. Studies have shown that miR-33a/b inhibit the expression of the cholesterol transporter ABCA1, which result of increased levels of atheroprotective plasma HDL. Mice models have shown that inhibition of miR-33 raise plasma HDL and support lowering of LDL.

miR-221 in hepatocellular carcinoma

miR-221/222 cluster has been reported to be over-expressed in multiple cancers, including hepatocellular carcinoma. miR-221 is reported to be expressed at a higher level than miR-222. The reason for the over-expression is unknown, however it was shown in human studies that the level of serum miR-221 in patients with hepatocellular carcinoma correlate with tumour size, stage and patient survival. This makes miR-221 important target in cancer research.

MicroRNAs definitely provide unique opportunity in drug development. Different studies show that microRNA inhibitors can have effect on different diseases.


Therapeutic modulation of microRNAs

Published on 2 Sep 2019

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

Could response-based dose be the future of patient care?

Could response-based dose be the future of patient care?

FDA report showed that most drugs are effective in only 25-62% of the patients. That probably make you wonder why they are approved and prescribed to patients? The answer to this question is not simple. Many approved drugs have a range of therapeutic dose which could be prescribed to the patients which allows clinicians to adjust the dose based on patient response and toxicity.

This variation of efficacy is another argument in support of precision medicine where patients are assessed based on their medical history, genetic background and other information in order to be provided with the optimal dose and the most adequate treatment for their condition.

What are the disadvantages of current clinical trial designs when it comes to dose individualisation?

Some small size clinical trials in specific indication like blood pressure, blood sugar, pain, seizure and coagulation could use different dose titration models to identify the best dose for the patients. However, large clinical trials often use fixed dose in their research.

Statistical model using data from clinical trials shows that in large clinical trials with fixed dose the response rate can vary between 20 and 80% while clinical trials with individually adjusted dose have much higher response rate.

Why cannot we simply use individualised dose instead of fixed dose?

While no doubt having option to adjust doses as per individual response would be the best solution to the problem there are some complications that prevent this.

  • For example if the drug is eliminated by kidneys and patient has renal function impairment they should be treated with lower dose to reduce the toxicity. And while this sounds like a logical decision the risk of giving the patient sub-optimal dose should also be considered.
  • This could not be done in oncology trials because the dose calculated is the maximal tolerated dose which is selected to maximise the effect.
  • Dose reduction is not an option for HIV drugs because of the high risk of drug resistance.
  • Drugs for slow progressing disease which require extended treatment also cannot be assessed adequately for efficacy.
  • Acute conditions which require one-off treatment cannot use dose titration.

There are several considerations for cases where dose titration is possible:

  1. The condition has to be stable to allow efficacy assessment.
  2. The drug should rapidly achieve steady pharmacokinetic and pharmacodynamics state otherwise the clinical trial will be very long considering the patients have to take more than 1 dose.
  3. Efficacy and toxicity should be quantifiable and relevantly stable once steady state is reached.
  4. The response to the drug should have quick onset and offset to avoid washout period.
  5. There should be an upper limit of dose-escalation to ensure patient safety.
  6. Subtracting the response of placebo – for example, patients could expect better response at higher doses and this could increase the efficacy of placebo arm.
  7. The treatment duration will be longer because patients will need more than one dose and this could increase the risk of drop out.

While dose titration has its challenges it has future in precision medicine and it is a logical option when assessing patients’ treatment.


The remarkable therapeutic potential of response-based dose individualisation in drug trials and patient care

Published on 1 Aug 2019

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

Adopting orphan drugs in different therapeutic areas

Adopting orphan drugs in different therapeutic areas

What happens if a newly developed drug fails in the tested indication?

Very often such drugs are abandoned if the developers think they will not be able to be used for different indications or therapeutic areas. In such cases these drugs are classified as ‘orphaned drugs’.

Where the term ‘orphaned drug’ comes from?

The focus of drug development is shifting towards diseases that affect smaller amount of the population, also known as rare or ‘orphan’ diseases. In USA a disease is considered ‘orphan’ if affects less than 200 000 people or roughly 1 per 1500 people. The term ‘orphan drug’ refers to drugs used to treat orphan diseases and its derived from legislation like Orphan Drug Act of 1983.

Not surprisingly oncology is viewed as one of the major therapeutic area where orphan drugs are used because more and more evidence suggest that cancer is a collection of orphan diseases.

Vicus Therapeutics has developed a model which allows adoption of such orphan drugs for new cancer indications.

Step 1:  Hierarchical Network Algorithm (HiNET) – This is an algorithm that allows modelling of the disease by evaluating tissue energetics, homeostatic control and biochemical pathways.

Step 2: Drug Selection: In this step it is used a data base which contains information for off-patent drugs, their target and human efficacy data in similar diseases, potential adverse events and pharmacokinetic profiles.

Step 3: Due to the complexity of cancer rarely one single drug could be used, therefore the model created potential treatment regimens.  Then the suggested regimens are evaluated for their potential safety and efficacy.

The use of such models in repurposing the orphan drugs is a novel and smart way of speeding up drug development process and identifying new therapies for rare diseases which in many cases have no treatment options.


Adopting orphan drugs: developing multidrug regimens using generic drugs

Published on 4 July 2019

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

Benefits and Challenges of Developing Companion Diagnostics

Benefits and Challenges of Developing Companion Diagnostics

Personalised medicine is a very popular topic in healthcare as a path towards better and cost-effective treatment of patients. However, we are not there yet due to various reasons. One of the major reasons is lack of diagnostic tests that will equip clinicians with the correct tools to make the right medical decisions.

In this review we will discuss the benefits and challenges of developing diagnostic tests or so called companion diagnostic devices which provide information regarding safety and efficacy of the corresponding therapeutic product.

What could be the benefits of companion diagnostics?

  • They help identify patients who will respond better to the therapy; have fewer side effects and improve their quality of life;
  • They allow clinicians to identify the best treatment options for their patients, save time and money from unnecessary procedures and treatments;
  • They will help regulatory agencies to better understand and evaluate the safety and efficacy of new therapies;
  • They will allow improving drug development timelines and reducing costs.

These are some of the benefits of having powerful diagnostics to help make decisions regarding patients’ treatment.

What kind of challenges are there for developing companion diagnostics?

  • In cases where there is limited information about the disease or the mechanism of drug action developing companion diagnostics could be a serious challenge;
  • Often drug development and diagnostics development follow their own pathways which means that by the time the drug reaches phase 3 the diagnostics may not be ready to be used to select the correct patient population;
  • The reliability of the test is also important – high prevalence of false positive or negative results will compromise its use;
  • Current healthcare systems often do not reimburse the full costs of such tests which discourage their usage;
  • The laws for intellectual property are different for companion diagnostics and often they allow creation and marketing of cheaper but not validated tests;
  • Companion diagnostics are regulated differently than medicinal products, which mean there could be significant delay before they reach the market.

While there are definitely challenges in developing companion tests they are the future of precision medicine so we hope we can see changes that will provide greater support for developing and testing companion diagnostics.


Developing companion diagnostics for delivering personalised medicine: opportunities and challenges

Published on 3 June 2019

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe