PSMA is a membrane glycoprotein which is expressed on the Prostate Cancer Cells. It expressed on normal Prostate Cells also but in Prostate Cancer Cells it is expressed many many times more than the normal Prostate Cancers Cells. Also, as the Prostate Cancer becomes more Castrate Resistant or Hormone Resistant, the expressions of PSMA increase. So, the more aggressive the Prostate Cancer the more is the expression of PSMA. And this PSMA serves as a brilliant target for us to both image as well as to treat patients of Prostate Cancer. So, when we talk about Imaging, we use a radioisotope like Gallium 68 or F-18 which emits rays which we can use for imaging. And these radioisotopes are labelled with a small body which targets these PSMA receptors which are expressed on the tumour cells.
So, this combination of the radio isotope with the small body is known as a radioligand. And this radioligand is injected intravenously and inside the body of a patient it seeks out all the sites of prostate cancer and its metastasis it accumulates, it gets attached to the PSMA receptors which are expressed on the prostate cancer cells it is internalized this radioligand complex is then internalized within the cell and it stays there and because of the radioactive tail which this radioligand has it emits certain rays which are then picked up by the Pet CT-Scan. And these images are then co-register to very high-resolution CT Scan images to give us a holistic picture of both, the extent of disease as well as detecting all the sites where this prostate cancer has metastasised. So, this serves as a invaluable tool for determining whether the patient is eligible for a treatment which addresses just the prostate gland or in cases where there is some spread the patient may actually need to going for a systemic therapy as compared to a local therapy like surgery or like radiation.
Now the same PSMA receptor may be used for treating patients of prostate cancer especially those patients who have become castrate resistant or hormone resistant. Now in these kind of tumours the use of this radioligand is for treating these tumour sites and hence the radio isotope which is used may be a beta or an alpha emitting radioisotope which has the potential to actually cause DNA breaks in the tumour cells resulting in their cell death. So now the common radioisotopes which are used for this radioligand therapy are Lutetium which is Lutetium 177 or in cases of an Alpha PSMA Therapy it is Actinium 225 which is used as the radioisotope.
Now what is the difference between alpha and beta.
The potency of cell kill is much higher with an alpha emitting radioisotope as compared to the beta emitting radioisotope. The alpha emitting radioisotopes when they emit the alpha rays these alpha rays cause double stranded breaks in the tumour DNA which is very difficult for the tumour cell to repair and as a result there is programme cell death and the tumour finally you know that particular tumour cell dies off. Whereas with the beta emitting radioisotope the since these beta cells cause single stranded breaks in the tumour DNA the tumour cell is sometime able to actually repair these break and continue to survive despite the Lutetium or the beta emitting radioligand therapy.
So, why use only beta why not use alpha in every patient. The problem is that with the beta emitting radioisotopes it is a much gentler form of treatment so the adverse effects are much less when you talk about beta PSMA therapy as compared to alpha PSMA therapy. And what are those adverse effects. The most critical adverse effect of radioligand PSMA based therapy is what we called in technical language a Xerostomia or a salivary gland toxicity. So, Xerostomia means a Dry Mouth. Now these PSMA receptors are also expressed in the salivary glands of a person physiologically. So, there is this is just a the physiological expression of PSMA receptors in the salivary gland.
Now when we use radioligand therapies which are directed towards PSMA receptors they will also effect the salivary glands of the patient and cause certain amount of fibrosis in the salivary gland which causes the patient to have a dry mouth. And this dry mouth is to us large extent non reversible. And this causes an impact to the patients quality of life. And this Xerostomia or dry mouth is far more with the alpha emitting agent as compared to the beta emitting agent and this is the reason why we often use beta emitting agents or lutetium PSMA as a first line of therapy and alpha emitting radioisotopes only in those patients who have become refractory to the Lutetium or the beta emitting radioisotopes.
About 75% of patients who are treated with lutetium PSMA will respond to Lutetium PSMA Therapy and often the duration of response is about 1 to median duration of response is about 1 to 1 and a half years. Now, When I talk about median that means that’s the most common duration of response to Lutetium PSMA. There are patients who may remain in disease control for a longer period, sometimes I even have patents who have completed more than 3 years of progression free survival or their may be a subset of patient’s which who have a recurrence or a progressive disease at a shorter interval.
So, there are lot of factors which are involved in this, what is the expression of PSMA in the tumour cells, what are the treatments which the patient has had till date, what is the general condition of the patient and most importantly what is the tumour biology. So, we know some aspects of disease. There are many aspects of disease which we are still finding out and so sometimes its not always possible to exactly say that which are the patients who will respond better as compared the those who will not. However typically the patients who have not received chemotherapy or are earlier on in their disease will respond better as compared to those who have already received chemotherapy or cytotoxic chemotherapy in the form of the taxanes. So, the patients who come to us post chemotherapy typically don’t do as well as patients who come to us prior to chemotherapy.