Platinum-based chemotherapy treatments are the mainstay treatment for many types of cancer.

Yet, alongside their effective potency in killing cancer cells, these therapies have well-recognised drawbacks that not only limit the ability for the treatment to kill cancer cells but can also cause patients to stop their cancer treatment altogether.

It’s a ‘Catch 22’ in oncology that presents a triple-edged unmet clinical need: how can we design a drug that minimises severe toxic side effects for patients and overcomes drug resistance, without compromising its ability to kill cancer cells?

Why does platinum-based chemotherapy cause severe toxic side effects?

Perhaps the most recognised drawback of platinum-based chemotherapy is the severe toxic side effects suffered by cancer patients as they undergo treatment.

Platinum-based therapies have a poor therapeutic ratio, meaning there is little difference between a toxic dose and an efficacious dose.

In addition to this is the poor specificity of platinum-based chemotherapy, which means the drug damages or kills both cancerous cells and healthy cells in the body. The damage done to healthy cells and tissues is what causes the severe toxic side effects widely known to be synonymous with chemotherapy.

This indiscriminate toxic effect of platinum-based drugs is why doses of chemotherapy must be limited when treating patients, as a dose that is too high would cause lethal harm to the patient, yet on the other hand too low a dose won’t be efficacious enough to kill cancerous cells.

Among major systemic toxicities with platinum-based therapy is the dose-limiting side effect of neurotoxicity, which describes altered or disrupted activity of the nervous system. Neurotoxicity can lead to a host of severe symptoms including vision loss, limb paralysis and reduced cognitive function, and is associated with the widely used oncology drug oxaliplatin.

Other common and well-known side effects of platinum-based chemotherapy include nausea, vomiting, diarrhoea, stomatitis (inflammation of mouth and lips) pain, mucositis (painful inflammation and ulceration of mucous membranes lining the digestive tract), alopecia (hair loss), anorexia (loss of appetite), cachexia (loss of skeletal muscle mass), asthenia (lack of energy/fatigue), anaphylaxis, cytopenia’s (low levels of various blood cells), ototoxicity, hepatotoxicity and cardiotoxicity.

While patients experiencing these side effects are extensively monitored and can be treated with other therapeutic agents, the toll these side effects can take on the patient’s overall health may require discontinuing their platinum-based chemotherapy altogether. This is the heartbreaking reality for oncologists in their treatment decisions for their patients; the delicate weighing of whether the tumour or the treatment is putting the patient most at risk of death.

How do tumours become resistant to drugs?

When doses of platinum-based chemotherapy must be limited to preserve the safety of the patient, this unfortunately contributes to another key challenge: platinum drug resistance.

Another complicating factor in treating many types of cancer is that cancer cells have the ability to develop a resistance to platinum-based drugs, which eventually renders the platinum-based therapy ineffective, resulting in treatment failure and subsequent cancer related death.

Drug resistance in general is a common clinical problem, impacting the effectiveness of many oncology agents in treating many types of cancers. Tumours have an inherent ability to evolve after exposure to the drug therapy. This is an unfortunate dilemma since the therapeutic process destroying cancerous cells can result in eventual drug resistance. This is why a combination of different drugs are typically used to combat the drug resistance of certain types of cancer. 

An example of drug resistance significantly impacting the efficacy of cancer treatment can be seen in ovarian cancer patients, for whom platinum resistance is a particularly limiting factor. This resistance typically occurs when there is tumour progression during or within six months of completing an initial platinum-based therapy treatment. When the disease is at an advanced stage, 80-90% of women with ovarian cancer will develop platinum resistance, which means platinum-based chemotherapy becomes ineffective, even if the patient showed promising results during initial treatment. For these patients, there is very little hope for survival.

There are many underlying molecular mechanisms seen in platinum-resistant tumours, which are multi-factorial.

In summary, these mainly include:

  1. A decrease of platinum accumulation in cancerous cells (i.e., not enough platinum accumulates inside the cell to kill it);
  2. Prevention of the platinum-based drug from forming platinum-DNA adducts, which are pieces of DNA bound to the platinum-based drug. These are key to blocking malignant cell proliferation in exerting the drug therapy’s cytotoxic/DNA damaging effects;
  3. Increased DNA repair processes of cancerous cells, even where adequate platinum-DNA adducts have formed;
  4. Decreased apoptosis (cell death);
  5. Activation of autophagy, which is a recycling mechanism within cells important to maintaining cellular homeostasis (a stable internal state). This is a mechanism that allows cells to endure metabolic and therapeutic stresses and has a significant influence on the efficacy of therapy as well as platinum resistance.

The urgent unmet need for a better platinum-based cancer drug

The continued research and development of new oncology drug candidates with different or improved mechanisms of action to destroy drug-resistant cancers across all solid tumour types is essential.

There is a critical need for the development of a cancer therapy which can overcome platinum-based resistance and minimise dose-limiting severe toxic side effects. Additionally, it is important to note the proven potency of platinum in killing cancer cells. Delivered in a more efficacious way that allows the drug to kill cancer cells with minimal harm to healthy cells, platinum-based drugs still provide promise to treat many types of cancer.

As such, there is a pressing unmet need for this treatment to be targeted, whereby the drug is specifically delivered to tumours, enabling the required higher doses for optimal clinical efficacy and with minimal toxicity to the patient’s healthy cells.

In response to this need, research is progressing for OxaliTEX – a first-in-class oncology drug candidate in development for treating platinum-resistant ovarian cancer. This will be the first clinical use of OxaliTEX for which its application to treat other types of cancer is also planned.  

Pre-clinical studies have shown OxaliTEX:

  • localises only in solid tumours;
  • enables visualisation of the tumour/s it has selectively localised in (MRI-detectable); 
  • activates once inside the tumour;
  • overcomes multifactorial platinum-resistance, which is why patients become resistant to platinum-based therapies;
  • increases cancer cell uptake of platinum, enhancing drug efficacy.

From landmark data published in the acclaimed journal Proceedings of the National Academy of Sciences (PNAS), OxaliTEX shows substantial promise  – not just for the near 300,000 women who are diagnosed with ovarian cancer every year globally, but for a much needed change to the way cancer therapy is delivered to patients as we know it.

Athena Kolivos

Chief Scientific Officer, CRC and Farmaforce

About OxaliTEX

OxaliTEX is a next generation oncology drug candidate that targets solid tumour cells, activates only within tumours and overcomes multi-factorial drug resistance mechanisms with minimal adverse effects. OxaliTEX is a conjugate of oxaliplatin – a well-established platinum-based chemotherapy drug – and a tumour localising texaphyrin for targeted drug delivery to cancerous tumours. Read more.

About OncoTEX Inc.

OncoTEX Inc. is an oncology company and member of bioscience investment enterprise The iQ Group Global. OncoTEX Inc. is developing TEX Core, a novel oncology drug platform that enables the development of well-tolerated, MRI-detectable cancer therapeutics that target drug-sensitive and drug-resistant solid tumours. Find out more.

About The iQ Group Global

The iQ Group Global is a bioscience investment enterprise that finds, funds and develops life science discoveries to create life-changing medical innovations. Find out more.