How should I answer this question ?

Question

Okay so this is the backround: A 45 year-old woman complaining of breast pain was diagnosed with having HER2-positive breast cancer. The patient underwent lumpectomy followed by a period of chemotherapy including adjuvant treatment. Over the course of their treatment, the patient developed a urinary tract infection that required antimicrobial therapy, which initially consisted of a trimethoprim/sulfametoxazole combination drug. However, the patient during the course of her therapy suffered multiple recurrent infections and was, consequently, enrolled in a clinical trial to test the efficacy of a new mannoside anti-infective agent.

And this is the Question: Discuss the mechanisms underpinning current therapeutic strategies for treating HER2-positive breast cancer. In your discussion, you should include details about managing therapeutic resistance and adverse side effects such as cardiotoxicity.

My question is that this question asks me to write about therapeutic resistance what is that mean?

Answer 1

Therapeutic resistance is evolution by the target cells in response to selective pressure exerted by the therapeutic method, in this case: pharmaceuticals. It occurs readily in cancer cells because they are both rapidly proliferating and subject to selective pressures. Long story short, they evolve due to the non-random reproductive success of variants that are better suited to resist induced apoptosis from pharmaceutical interventions.

Human epidermal growth factor receptor-2 (HER2) is a transmembrane receptor that dimerizes before binding intracellular proteins that trigger signalling cascades that enable a cell to proliferate, survive, invade tissue, and promote angiogenesis. These are all processes that are inhibited in most non-cancerous cells. So activation of HER2 is a problem. Trastuzumab is a monoclonal IgG antibody that binds to HER2 and blocks its activation. Unfortunately in around 50% of metastatic breast cancers treated with this drug, resistance develops.

The source of resistance is random mutatation combined with non-random survival, aka evolution by natural selection. With trastuzumab blocking HER2, resistance evolves to allow HER2 to function within the presence of trastuzumab. This can happen in a few ways: 1. Upregulation of alternative signalling pathways from other receptors that produce the same end-products as HER2; 2. Creation of a truncated HER2 protein that lacks the trastuzumab binding site; 3. Increased expression of membrane-associated glycoprotein mucin-4 (MUC4), which partially covers the binding site of trastuzumab. There are other mechanisms of resistance in this case, not all of which are understood, but with these examples I think the general idea of how resistance works should be clear.

I hope this was helpful!

Best,

PKW

Answer 2

Hi Elena G. (again!),

Therapetic resistance is the condition that a tumor under treatment (with a drug, these days!) initially was responding by shrinking, but then starts to grow again. Some cells of the tumor were not stopped by the drug dosage applied, and they continued to multiply, hence the tumor as a whole grew. Since tumor cells frequently mutate in both small and large ways, this is particularly a problem with metastases, which may have different drug response profiles than their parent tumor mass. The growth of metastases is frequently being suppressed by the parent tumor, and if it is surgically removed, the metastases may explosively proliferate. Therefore, it is desirable to assess metastases and attempt to kill them chemically *before* removing the parent tumor.

Many chemotherapetic agents have narrow safety indices (toxic level divided by effective level) for heart, kidney, liver, etc. tissues. Not to mention digestive system lining, hair follicles, etc.

You should be able to find lots of discussions in articles and in textbooks, on this topic?

-- Cheers, -- Mr. d.