Neutral evolution of drug resistant colorectal cancer cell populations is independent of their KRAS status

Emergence of tumor resistance to an anti-cancer therapy directed against a putative target raises several questions including: (1) do mutations in the target/pathway confer resistance? (2) Are these mutations pre-existing? (3) What is the relative fitness of cells with/without the mutation? We addressed these questions in patients with metastatic colorectal cancer (mCRC). We conducted an exhaustive review of published data to establish a median doubling time for CRCs and stained a cohort of CRCs to document mitotic indices. We analyzed published data and our own data to calculate rates of growth (g) and regression (d, decay) of tumors in patients with CRC correlating these results with the detection of circulating MT-KRAS DNA. Additionally we estimated mathematically the caloric burden of such tumors using data on mitotic and apoptotic indices. We conclude outgrowth of cells harboring intrinsic or acquired MT-KRAS cannot explain resistance to anti-EGFR (epidermal growth factor receptor) antibodies. Rates of tumor growth with panitumumab are unaffected by presence/absence of MT-KRAS. While MT-KRAS cells may be resistant to anti-EGFR antibodies, WT-KRAS cells also rapidly bypass this blockade suggesting inherent resistance mechanisms are responsible and a neutral evolution model is most appropriate. Using the above clinical data on tumor doubling times and mitotic and apoptotic indices we estimated the caloric intake required to support tumor growth and suggest it may explain in part cancer-associated cachexia

Estudio de factores pronósticos, predictivos de respuesta y nuevas dianas terapéuticas en pacientes con cáncer rectal localmente avanzado

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina. Departamento de Medicina. Fecha de lectura: 20 de Abril de 2009

Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats

Cisplatin is an anticancer agent marred by nephrotoxicity; however, limiting this adverse effect may allow the use of higher doses to improve its efficacy. Cilastatin, a small molecule inhibitor of renal dehydropeptidase I, prevents proximal tubular cells from undergoing cisplatin-induced apoptosis in vitro. Here, we explored the in vivo relevance of these findings and the specificity of protection for kidney cells in cisplatin-treated rats. Cisplatin increased serum blood urea nitrogen and creatinine levels, and the fractional excretion of sodium. Cisplatin decreased the glomerular filtration rate, promoted histological renal injury and the expression of many pro-apoptotic proteins in the renal cortex, increased the Bax/Bcl2 ratio, and oxidative stress in kidney tissue and urine. All these features were decreased by cilastatin, which preserved renal function but did not modify the pharmacokinetics of cisplatin area under the curve. The cisplatin-induced death of cervical, colon, breast, and bladder-derived cancer cell lines was not prevented by cilastatin. Thus, cilastatin has the potential to prevent cisplatin nephrotoxicity without compromising its anticancer efficacy

Comparison of growth rate (<i>g</i>) using tumor measurements from Diaz et al [17] and from an independent CRC tumor data set of patients treated in second line with conventional chemotherapy.

<p><b>Top 2 panels:</b> The growth (g, p = 0.244) and regression (<i>d</i>, p = 0.858) rates of tumors treated with panitumumab in which mutant <i>KRAS</i> DNA could be detected in serum (MT) do not differ from those of tumors without detectable mutant <i>KRAS</i> DNA in serum (WT). <b>Lower 2 panels:</b> Compared to tumors independently treated in second line with conventional chemotherapy the growth rates (<i>g</i>) of the panitumumab-treated tumors is similar for both the subgroup with detectable circulating mutant <i>KRAS</i> DNA (MT) in serum and those without detectable mutant <i>KRAS</i> DNA in serum (WT).</p

Tabulation of mitosis in colorectal cancers.

<p>Tabulation of mitosis in colorectal cancers.</p

Evolution of tumors in patients is shown as graphs of RECIST measurements.

<p><u><b>A</b>:</u> Nine patients with detectable MT <i>KRAS</i> DNA in serum. <u><b>B</b>:</u> Nine patients without detectable MT <i>KRAS</i> DNA in serum. As can be seen the kinetics of tumor regression and growth of these tumors is indistinguishable. Detection of a mutant <i>KRAS</i> DNA is serum, interpreted as evidence of “acquiring” this genetic alteration, does not impact the growth of the tumor. The blue lines are the lines drawn by the model and this demonstrates how well the theoretical (blue line) fit the actual (red symbols). The fit of the actual data to the theoretical had p values less than 0.05 in all cases, and in most much less than that.</p