NEW BIOMARKERS ARE NEEDED - URGENTLY!

One of the dreaded complications of chemotherapy is Pulmonary fibrosis or interstitial pneumonitis which ultimately takes the patient's life when Complete Response may have been achieved.   It is a dramatic event in the life of our patients, many survive and many have a limited fibrosis that allows life to go on after high doses of steroids.  Some patients suffer consequences of exposure to high dose steroids.   Suffice is to say that so far the Advisory committee has not called for any standard monitoring of this abnormal side effect, opting instead for a Head in the sand and crossing finger policy.  Oncologists hide behind the statement that the "patient was warned this could happen".  Knowing what we know, it is time to be rational about this and go after this side effect, understand it and monitor it carefully as we treat our patients!
So far repeated  pulmonary function testing has been our recourse in patients who are taking Bleomycin.  Those on Mitomycin, rarely do we give them a second dose...But when is comes to Gemzar for example, warning the patient that interstitial Pneumonitis could result, is all we do.  It is unclear whether what happens in the lung with Bleomycin Vs Gemzar is the same phenomenon at various intensities.  All we know is that the 2 phenomena both result in a limitation of lung function as a result of fibrosis.  Studies have suggested that the early use of Growth factors to maintain the hematologic status of the patient may exacerbate or increase the frequency/occurrence of pulmonary fibrosis. In the treatment of Hodgkin disease, we try to avoid prompt use of growth factors to that end!
Fibrosis involves cyclins for sure, but no one has come forward to propose a clear Interleukin or other to be monitored as we treat our patients.  The call for new bio-markers is therefore appropriate and pertinent!  Something is happening in our patients at various levels, let's go and define it pronto instead of clinging to lingering politics of prayers, crossing the fingers and keeping our head in the sand !

Secondary Hematologic Malignancies

Japanese researchers suggested in a retrospective study of patients treated with Temodar for Glioma, that there is an increased occurrence of secondary Myelodysplasia, leukemias and particularly Acute Lymphoblastic Leukemia.  It is interesting to look further, beyond the simple observation and speculate as to what leads to such a transformation at the gene level.
Leukemias are a disease not only of pathways, but of deep derangement at the Histone-DNA level and include particularly not only protein complexes similar to core binding factors, but also regulator genes which appear to be specifically amplified in leukemias!
It is pertinent to also look closer at Proteins Kinases affecting or interacting with DNA.  Temodar is an Alkylating agent per the researcher's report.
The interval between the treatment and the occurrence is also interesting, and suggests that the secondary Leukemia results from a secondary amplification of proliferative genes after the onslaught on cellular receptors by the chemical stimulus. The NK-kB, c-JUN must be in play.  Blocking these pathways could prevent such malignant occurrence. We will soon find that secondary malignancy could be prevented by simply blocking some tumor growth factors.  We don't need to accept these complications any more.  I learned that my first patient who was diagnosed with Hodgkin disease, a curable disease, died later on with an Acute Leukemia.  She was free of Hodgkin disease. Our current follow-up is inadequate in this regard, as we sit and wait for secondary leukemia to set in.  Lets look into blocking Tumor growth factors to stop secondary leukemias!

THE CRCBM RECOMMENDS THIS PIECE OF ARTICLE TO ALL READERS!

Mechanisms of Resistance to Anti-Angiogenic Therapy and Development of Third-Generation Anti-Angiogenic Drug Candidates

1. Sonja Loges*,
2. Thomas Schmidt* and
3. Peter Carmeliet⇓

+ Author Affiliations

1. Vesalius Research Center (VRC), Leuven, Belgium

1. P. Carmeliet, MD, PhD, Vesalius Research Center, VIB, K.U. Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium Email: peter.carmeliet@med.kuleuven.be
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5. Suffice is to say that the concerns mentioned in this review, which is an excellent review, unveils in pretty good details the insufficiency of a monotherapy attacking an essential function of the cells. Not only will the cell have an answer such as dummy receptors, secondary amplification of transcription factors of growth factors, but escape mechanisms that include escape of the area leading to metastasis.  I should confess that recruiting other cells to help fight the attacker (Myeloid and endothelial cells) showed clearly how much angiogenesis is globally needed.  I would think that the reaction by the NF-kB would be sufficient; with its secondary growth  factor production, induction would be the predictable way.  But clearly, the cell wants restoration of the angiogenic function and finally wins, making Avastin effects short lived.  By inducing Hypoxia, stress becomes a secondary impetus and c-JUN enters the dance and fights again with resulting amplification of growth factor and various dislocation of various cyclins at integrin locations including the Angiopoietins.
6. One of the things that needs to be emphasized or not looked at or discussed in your piece are events happening at the MEK.  You know by now that MEK is clearly amplified either by the cancerous process or in reaction to the blockage or consumption at VEGF.  Tracking MEK is important, because if amplified and mutated it may reverse mesengial transformation and render the cell more omnipotent.  It may be at the center of the observation that blocking both EGFR and VEGF reduces the progression free survival. Events at the MEK need to be scrutinized.
7. You also realize that, in the long run,  MTOR will be secondarily stimulated leading to Telomere preservation (stabilization) and cell surviva
8. The quick restoration of the angiogenic function after cessation of the treatment marks the importance of VEGF.

Your discussion has not only brought up in details the predicted failure of mono-target-therapies, but in the case of an important/critical cellular function being impaired by Avastin, and the resulting multitude of cellular responses. I really thank the authors for this important piece!
Clearly, Avastin is never meant to be a monotherapy, that is the answer!  To all action, there is a reaction. And cells expect action, it is built for them!